EP3725771A1

EP3725771A1 - Alk protein degradation agent and anti-tumor application thereof

Info

Publication number: EP3725771A1
Application number: EP18888217.9A
Authority: EP
Inventors: Xiaobao Yang; Biao Jiang; Xiaoling Song; Haifan Lin; Ning Sun; Jinju CHEN; Xing Qiu; Chaowei REN; Ying KONG
Original assignee: ShanghaiTech University
Current assignee: ShanghaiTech University
Priority date: 2017-12-13
Filing date: 2018-12-12
Publication date: 2020-10-21
Also published as: WO2019114770A1; KR102538307B1; CN109912655A; EP3725771A4; JP2021506820A; US20200306273A1; CA3085645A1; AU2018382122B2; AU2018382122A1; KR20200108838A; US11771709B2; JP2022174114A; CA3085645C; CN109912655B

Abstract

A compound of formula (I) and its antitumor application are disclosed. The compounds of formula (I) have degradation and inhibitory effects on ALK target proteins. They are mainly composed of four parts: the first part, ALK-TKI, being compounds with ALK tyrosine kinase inhibitory activity; the second part, LIN, being different kinds of linker (Linker); the third part, the ULM, being a small molecule ligand (ULM, ubiquitin ligase binding moiety) with ubiquitination of VHL, CRBN or other proteases; and the fourth part, the group A, being a carbonyl group or absent, which covalently bond ALK-TKI to LIN, wherein LIN and ULM are covalently bonded. A series of compounds designed and synthesized by the present disclosure have wide pharmacological activities, have functions of degrading ALK protein and inhibiting ALK activity, and can be used for related tumor treatment.

Description

Field

The present disclosure relates generally to compounds of formula (I) for cancer prevention and therapy, and their use in anti-cancer therapy, especially against cancer-related proteins including ALK, ROS1, EGFR and FLT3.

Background

Lung cancer is the leading cause of cancer related death in China and the world wide. In China, the incidence of lung cancer is already surpassed other types of cancer, and each year there are about 800,000 people died from lung cancer. The five-year survival rate of lung cancer is also very low, and it is only about 17%. And this rate havn't change too much since 70s in the last century. This is because traditional chemotherapy and radio-therapy killed normal cells together with cancer cells, which causes decreased immunity and dysfunction of patients physiology. Recently precision medicine provides targeted therapy to patients with specific driver genes which greatly reduced the toxic effect of traditional chemotherapy and radio-therapy and greatly improved patients quality of life.
Treating ALK (Anaplastic Lymphoma Kinase) mutation positive non-small cell lung cancer with specific small molecular tyrosine kinsae inhibitors greatly improved the efficacy of cancer therapy and patient quality of life. According to the pathological classification, lung cancer can be divided into small cell lung cancer and non-small cell lung cancer. The latter accounts for about 80% of the total number of lung cancer patients. In lung cancer, patients with EML4-ALK gene fusion are about 3-7% of the total number of non-small cell lung cancer patients. The incidence ratio has no significant difference between Asian and western caucasion populations. In clinics, such mutations are often observed in young non-smoker patients (Soda et al. 2007; Nishio et al. 2017; Chan et al., 2017). ALK is a typrosine receptor kinase. Gene fusion of this gene is a strong cancer driver gene which was firstly discovered in anaplastic large cell lymphoma patients, and later were found in many other diseases including diffused large B-cell lymphoma and Inflammatory Myofibroblastic Tumor (IMT) (Wellmann et al., 1997). ALK forms fusion genes with different partners and leads to consitutively activated ALK kinase activities to transform normal cells become cancer cells(Soda et al., 2007; Choi et al., 2008; Cha et al., 2016). In lung cancer, the major fusion partner with ALK is Echinoderm microtubule-associated protein-like 4, EML4. ALK also can form fusion proteins with many other different partners, such as KIF5B, to drive cancer formation (Takeuchi et al. 2008). Such ALK fusion positive cancer cells are highly dependent on ALK kinase activities and inhibition of ALK kinase activity leads to the death of such cells. Several ALK kinase inhibitors have been approved to treat ALK mutant positive cancer. In 2011, Crizotinib developed by Pfizer was approved by FDA to treat ALK positive non-small cell lung cancer. In 2016, Crizotinib was approved to treat non-small cell lung cancer patients with ROS1 (c-ros oncogene 1 receptor tyrosine kinase,c-ros) mutation. With this drug, the progression free survival of the patients was increased to about 10 months (Nishio et al, 2017). Regardless of with or without pretreatment, Crizotinib showed greater benefit to patients. It increased median progression free survival from 7.2 months with chemotherapy to 9.6 months, and which was increased to 13.6 months in Asian patients (Nishio et al., 2017). And the objective response rate was increased from 20% to 65% comparing those treated with chemotherapy. Treating ALK fusion positive patients with specific tyrosing kinase inhibitors provides great benefit to patients in clinics and it made a new milestone in lung cancer therapy.
ALK gene fusions play important roles in non-small cell lung cancer, ALK fusion mutants are also frequently found in anaplastic large cell lymphoma (ALCL), and mostly present in the form of NPM-ALK fusion form. Through improved clinical diagnostic methods, ALK has been found to form fusion mutations with dozens of other genes. The fusion protein produced by ALK gene fusion highly activates ALK kinase activity, and is also very sensitive to ALK inhibitors. Furthermore, ALK gene amplification and mutation were also reported in glioblastma. Some of these ALK mutations are also sensitive to ALK inhibitors, and potentially benefit from ALK inhibitor development.
Although there are great benefit for patients of using ALK kinase inhibitors in clinic, drug resistance eventually developed usually about one year after drug treatment initation. Part of the reason is due to ALK gene amplification or acquired resistance mutations in ALK protein, including L1196M, L1198F, L1152R, L1151TIN, C1156Y, F1174C, G1202R, ,D1203N, S1206Y (Bordi et al., 2017; Dagogo-Jack and Shaw, 2016; Drizou et al., 2017). The most frequent mutation is the Point mutation L1196M which was called gatekeeper mutation. Because Crizotinib is hard to reach brain, resistance was also developed after the occurance of brain metasis. Other resistance mechanisms are activation of other driver genes, including EGFR mutation or activation (30-35%), c-KIT amplification (10%) or Kras or other gene mutations (5%) (Bordi et al., 2017).
Studies on the drug resistance mechanisms promoted the development of the second generation of ALK kinase inhibitor drugs, which include Ceritinib (Novartis, LDK378), Alectinib (Roche, CH542802) and Brigtinib (Ariad, AP26113). These drugs can overcome many acquired resistance mutations in ALK, including gatekeeper mutation L1196M. In addition, these drugs can penetrate into the brain very well and inhibit the growth of brain metasized tumor. Within these drugs, certinib was approved by FDA in 2014 to treat patients progressed on Crizotinib treatment or patients who are not Crizotinib-tolerated. Second line treatment with Ceritinib increased progression free survival for about 4 months comparing to second line chemotherapy (Shaw et al., 2017). Alectinib was approved in 2014 in Japan and 2015 by FDA in US. It is about 10 fold more potent than Crizotinib in inhibiting ALK kinase activities. The advantage of second line using Alectinib over chemotherapy after Crizotinib resistance was recently reported (Asao et al., 2017). It increased the patients' progression free survival up to 35 months. This indicated that of using ALK kinase inhibitor drugs with optimized drug treatment strategies might make the uncontrolled tumor growth to a controllable chronic diseases. Brigatinib (Takeda) was firstly approved by FDA as breakthrough designation on April 28, 2017 for second line treatment ALK-positive patients who developed resistance to Crizotinib. Comparing to the other two other 2^nd generation drugs, Brigatinib not only effectively inhibited G1269A, C1156Y, I1171S/T, V1180L, it also blocked the resistance mediated by G1202R (Zhang et al., 2016). In addition, Brigatinib can blocked the activities of both ALK and EGFR, the repsonse rate is 55% and disease control rate was about 86%. Currently, it has been granted priority review as a first-line treatment for ALK positive non-small cell lung cancer.
Although the development of newer generation more specific tyrosine kinase inhibitor drugs showed high reponse rate in ALK mutant positive non-small cell lung cancer, drug resistance still occurrs. The 3^rd generation ALK kinase inhibitor Lorlatinib (PF-06463922) can overcome many known acquired ALK resistant mutations, but resistance to Lorlatinib eventually occurred in patients. The number of patients with ALK rearrangement mutation is big and it continues rising. Drug resistance to targeted therapy becomes a big obstacle to improve patients survival and does not fit the development need of the society. The need to overcome drug resistance is big and the developing need of new types of drugs to overcome resistance is urgent.
ALK gene fusions play important role in non-small cell lung cancer, ALK fusion mutations are also frequently found in anaplastic large cell lymphoma (ALCL), colorectal cancer (Lin et al., 2009; Lipson et al., 2012), IMT(Lawrence et al., 2000); ovarian cancer (Ren et al., 2012) diseases. ALK gene amplification and activating mutants were also reported in glioblastoma(Chen et al., 2008; George et al., 2008; Janoueix-Lerosey et al., 2008; Mosse et al., 2008). It has been found in the clinic that ALK can form fusion mutations with dozens of other genes, and most of them present as NPM-ALK fusion in ALCL. The fusion protein produced by ALK gene fusion highly activates ALK kinase activity, and is also very sensitive to ALK inhibitors.
Proteolysis targeting technology is a new strategy of drug design. Traditional small molecular design only inhibit the kinase activity of ALK protein, whereas the acquired resistant mutations on the protein are the basis of certain resistance mechanism. We utilize the platform of Proteolysis targeting drug (PROTAD) to develop new ALK targeting drugs. The action mechanisms of these drugs is distinct from traditional small kinase inhibitors. These PROTAD drugs not only inhibit the activity of target proteins such as ALK, but also are able to get rid of target proteins through proteolysis. By using the PROTAC technology, we would like to develop new drugs targeting cancer driver genes such as ALK fusion proteins and getting rid of these target proteins ultimately so as to treat cancer and overcome drug resistance.

Summary of the Invention

The present disclosure provides a compound of formula (I):
or its salts, enantiomers, stereoisomers, solvates, or polymorphs, wherein all substituents or groups are as defined in the detailed description of the invention.
The present disclosure also provides a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
The present disclosure also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament:
wherein all substituents or groups are as defined in the detailed description of the invention.
The present disclosure also provides the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof for the prevention and/or treatment of cancer, especially lung cancer.
The present disclosure further provides the use of the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing and/or treating cancer.
The Cancers include, but are not limited to, lung cancer, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer, Ros1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, EGFR-mutated non-small cell lung cancer; Lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma (ALCL), diffused large B-cell lymphoma; inflammatory myofibroblastic tumor (IMT); colorectal cancer; glioma, glioblastoma; Acute myeloid leukemia (AML); and ovarian cancer etc.
The present disclosure also provides a method for treating or preventing cancer, which comprises administering to a subject a therapeutically effective amount of said compound of formula (I), or a pharmaceutically acceptable salt thereof, or said pharmaceutical composition according to the present disclosure.

Brief Description of Drawings

Figure 1 shows the investigation of Brigatinib Analogue A-based PROTAD molecules according to the present invention in ALCL cell line SR;
Figure 2 shows the investigation of Brigatinib Analogue A-based PROTAD molecules according to the present invention in lung cancer cell line H3122;
Figure 3 shows the investigation of Brigatinib Analogue B-based PROTAD molecules according to the present invention in ALCL cell line SR;
Figure 4 shows ALK phosphorylation and protein degradation activities for Brigatinib Analogue B-based PROTAD molecules according to the present invention in lung cancer cell line H3122;
Figure 5 shows the investigation of Brigatinib Analogue B-based PROTAD molecules according to the present invention in lung cancer cell line H2228;
Figure 6 shows the investigation of Brigatinib Analogue C-based PROTAD molecules according to the present invention in ALCL cell line SR;
Figure 7 shows the investigation of Brigatinib Analogue C-based PROTAD molecules according to the present invention in lung cancer cell line H3122;
Figure 8 shows the investigation of the effects of Brigatinib Analogue C-based PROTAD molecules according to the present invention on the activation of ALK mediated signaling pathways in ALCL cell line SR and lung cancer cell line H2228;
Figure 9 shows the investigation of Alectinib Analogue A-based PROTAD molecules according to the present invention in ALCL cell line SR;
Figure 10 shows the investigation of Alectinib Analogue A-based PROTAD molecules according to the present invention in lung cancer cell line H3122;
Figure 11 shows the investigation of the effect of Ceritinib based PROTAD molecules according to the present invention on ALK protein in lung cancer cell line H3122;
Figure 12 shows the investigation of the effect of Crizotinib based PROTAD molecules according to the present invention on ALK protein and downstream signaling pathway in lung cancer cell line H3122;
Figure 13 shows that PROTAD molecules according to the present invention reduced ALK protein stability;
Figrure 14 shows time-dependent and concentration dependent effect of Brigatinib on ALK protein in SR cell lines;
Figure 15 shows that Brigatini-based PROTAD molecules according to the present invention degrade ALK protein in SR cell lines in the manner of time-dependent way;
Firgure 16 shows that the PROTAD molecules according to the present invention act through proteosome-mediated proteolysis pathway (SR cell line);
Figure 17 shows the effect of PROTAD molecules according to the present invention on cell colony formation abilities in lung cancer cell lines H2228;
Figure 18 shows the effect of PROTAD molecules according to the present invention on cell colony formation abilities in lung cancer cell lines PC9;
Figure 19 shows the effect of PROTAD molecules according to the present invention on cell colony formation abilities in lung cancer cell lines PC9Brc1;
Figure 20 shows the effect of PROTAD molecules according to the present invention on cell growth in colorectal cancer cell lines SW48.

Detailed Description of the Invention

The compounds of the present disclosure are very effective in degrading ALK tyrosine kinases associated with lung cancer in the cellular environment. These compounds of the present disclosure are based on PROteolytic TArgeted Chimeras (PROTAC) technology, in which one end of the compound is bound to VHL or CRBN protease with ubiquitination function, and the other end is bound to a targeted tyrosine kinase. When the compound of the present disclosure is combined with a tyrosine kinase and VHL or CRBN protease, a complex is formed, so that VHL or CRBN protease is in close proximity to the tyrosine kinase, resulting in the ubiquitination of the tyrosine kinase and its subsequent proteasome degradation.
Accordingly, in a first aspect the present disclosure provides a compound of formula (I):
or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof, in which:

ALK-TKIs is covalently connected to LIN via group A, and ULM is covalently connected to LIN;
wherein ALK-TKIs is an ALK tyrosine kinase inhibitor or an analogue thereof with the same function;
LIN is a linking group, which represents a linear or branched alkylene chain, a spiro-cycloalkylene, a 1,4-piperazinylene, or a 1,3-dialkynyl group, wherein the linear or branched alkylene chain is optionally interrupted one or more times by one or more selected from the group consisting of O, C(O)NH, NHC(O), NHC(O)NH, NH, S, sulfinyl, sulfonyl, aminosulfonylamino, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, or heteroarylene group, or any combination thereof, wherein the linear or branched alkylene chain is optionally substituted with one or more substituents; ULM is a small molecule ligand of VHL or CRBN protease with ubiquitination function; and
the group A is C(O) or absent.

In the present disclosure, the term "alkylene" (which is used interchangeably with "alkylene chain") used alone or in combination refers to a linear or branched divalent saturated hydrocarbon group composed of carbon and hydrogen atoms. The term "C_x-C_y alkylene" or "C_x-y alkylene" (x and y are each an integer) as used herein refers to a linear or branched alkylene group containing from x to y carbon atoms. The term C₁-C₃₀ alkylene group is preferably C₁-C₂₉ alkylene, or C₁-C₂₈ alkylene, C₁-C₂₇ alkylene, C₁-C₂₆ alkylene, C₁-C₂₅ alkylene, C₁-C₂₄ alkylene, C₁-C₂₃ alkylene, C₁-C₂₂ alkylene, C₁-C₂₁ alkylene, C₁-C₂₀ alkylene, C₁-C₁₉ alkylene, C₁-C₁₈ alkylene, C₁-C₁₇ alkylene, C₁-C₁₆ alkylene, C₁-C₁₅ alkylene, C₁-C₁₄ alkylene, C₁-C₁₃ alkylene, C₁-C₁₂ alkylene, C₁-C₁₁ alkylene, C₁-C₁₀ alkylene , C₁-C₉ alkylene, C₁-C₈ alkylene, C₁-C₇ alkylene, C₁-C₆ alkylene, C₁-C₅ alkylene, C₁-C₄ alkylene, C₁-C₃ alkylene, or C₁-C₂ alkylene. Representative examples of "alkylene" group include, but are not limited to, methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, peptacosylene, octacosylene, nonacosylene, and triacontylene.
In the present disclosure, the term "arylene" used alone or in combination refers to a divalent aromatic hydrocarbon group containing from 5 to 14 carbon atoms and optionally one or more fused rings, such as phenylene group, naphthylene group or fluorenylene group. In the present disclosure, the "arylene" is an optionally substituted arylene. A substituted arylene group refers to an arylene group substituted 1-3 times with a substituent(s) selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, halogen, amino, or hydroxyl.
In the present disclosure, the term "aryl" used alone or in combination refers to an aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally one or more fused rings, such as phenyl or naphthyl or fluorenyl . In the present disclosure, the "aryl" is an optionally substituted aryl. A substituted aryl refers to an aryl group substituted 1-3 times with a substituent(s) selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, halogen, amino, or hydroxyl.
In the present disclosure, the term "C_1-3alkoxy group" used alone or in combination refers to a linear or branched alkoxy group containing from 1 to 3 carbon atoms. Representative examples of C_1-3alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. Examples of C_1-3alkoxy are preferably methoxy and ethoxy.
In the present disclosure, the term "cycloalkyl" used alone or in combination refers to a saturated or partially unsaturated (e.g., containing one or more double bonds but not having a completely conjugated π-electron system) monocyclic or bicyclic cyclic hydrocarbon radical having from 3 to 12 carbon atoms. Representative examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, and spiro-cycloalkyl.
In the present disclosure, the term "cycloalkylene", used alone or in combination, refers to a saturated and partially unsaturated (e.g., containing one or more double bonds, but not having a fully conjugated π-electron system) divalent monocyclic or bicyclic cyclic hydrocarbon group having from 3 to 12 carbon atoms. Representative examples of "cycloalkylene" include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, and spiro-cycloalkylene.
In the present disclosure, the term "heteroarylene" used alone or in combination refers to a 5- to 10-membered monocyclic or bicyclic divalent aromatic ring group containing one or more (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Representative examples of such heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzoisoxazolylene, benzothiazolylene, benzoisothiazolylene, benzotriazolylene, benzo[2, 1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolylene, isoquinolylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo[1,5-a]pyridinylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2-a]pyridinylene, 1H-pyrrolo[3,2-b]pyridinylene, 1H-pyrrolo[2,3-b]pyridinylene, 4H-fluoro[3,2-b]pyrrolylene, pyrrolo[2,1-b]thiazolylene, and imidazo[2,1-b]thiazolylene. In the present disclosure, the heteroarylene group may be unsubstituted or substituted. A substituted heteroarylene group refers to a heteroarylene group substituted 1-3 times by a substituent(s) preferably selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, or hydroxyl.
In the present disclosure, the term "heteroaryl" used alone or in combination refers to a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one or more (eg, from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Representative examples of such heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-a]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, 4H-fluoro[3,2-b]pyrrolyl, pyrrolo[2,1-b]thiazolyl and imidazo[2,1-b]thiazolyl. In the present disclosure, the heteroaryl groups may be unsubstituted or substituted. A substituted heteroaryl group refers to a heteroaryl group substituted 1-3 times with a substituent(s) preferably selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, or hydroxyl.
In the present disclosure, the term "heterocyclylene" used alone or in combination refers to a 4- to 6-membered saturated monocyclic divalent cyclic hydrocarbon group containing one or more heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Examples of the heterocyclylene group include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, triazolylend, tetrahydrofuranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, and dioxanylene. In the present disclosure, the heterocyclylene group may be unsubstituted or substituted as explicitly defined. A substituted heterocycloalkylene refers to a heterocycloalkylene group substituted 1-3 times by a substituent(s) which can be preferably selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, or hydroxyl.
In the present disclosure, the term "heterocyclyl" used alone or in combination refers to a 4-to 6-membered saturated monocyclic monovalent cyclic hydrocarbon group containing one or more heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Examples of the heterocyclyl group include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, triazolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and dioxanyl. In the present disclosure, the heterocyclyl may be unsubstituted or substituted as explicitly defined. A substituted heterocyclyl group refers to a heterocyclyl group substituted 1-3 times with a substituent(s)which can be preferably selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, or hydroxy.
In the present disclosure, the term "spiro-cycloalkylene" used alone or in combination refers to a divalent alicyclic hydrocarbon group derived by removing two hydrogen atoms from afree valence carbon atom(s) of the alicyclic hydrocarbon group in which two rings share one common carbon atom. Representative examples of spiro-cycloalkylene group include, but are not limited to, spiro[3.3]heptanylene (for example
), spiro[4.5]decanylene, spiro[5.5]undecanylene, 4-methylspiro[2.4]heptanylene etc.
In the present disclosure, the term "alkynylene" used alone or in combination refers to a linear or branched divalent hydrocarbon group containing one or more carbon-carbon triple bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4) carbon atoms. Examples of the alkynylene group include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.
In the present disclosure, the term "alkynyl" used alone or in combination refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and containing 2 to 10 (e.g., from 2 to 6, or from 2 to 4) carbon atoms. Examples of the alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1,3-dialkynyl.
In the present disclosure, the term "alkenylene" used alone or in combination refers to a linear or branched divalent hydrocarbon group containing one or more carbon-carbon double bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4) carbon atoms. Examples of the alkenylene group include, but are not limited to, vinylidene (e.g., -CH=CH-), 1-propenylene, and 1-butenylene.
In the present disclosure, the term "alkenyl" used alone or in combination refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4) carbon atoms. Examples of the alkenyl group include, but are not limited to, vinyl, 1-propenyl, and 1-butenyl.
In the present disclosure, the term "halogen atom" or "halogen" used alone or in combination refers to fluorine, chlorine, bromine or iodine, and is preferably F, Cl or Br.
In the present disclosure, the term "alkyl" used alone or in combination refers to a linear or branched alkyl group. The term "(C_x-C_y) alkyl" or "C_x-y alkyl" (x and y are each an integer) as used herein refers to a linear or branched chain alkyl group containing from x to y carbon atoms. The term "C_1-10 alkyl" used alone or in combination in the present disclosure refers to a linear or branched chain alkyl group containing from 1 to 10 carbon atoms. The C_1-10 alkyl group of the present disclosure is preferably a C_1-9 alkyl group, or a C_1-8 alkyl group, or a C_2-8 alkyl group, or a C_1-7 alkyl group, or a C_1-6 alkyl, C_1-5 alkyl, or C_1-4 alkyl. Representative examples of the alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl and decyl. The term "C_1-3 alkyl group" in the present disclosure refers to an alkyl group containing from 1 to 3 carbon atoms, and its representative examples include methyl, ethyl, n-propyl, and isopropyl.
In the present disclosure, the "alkyl" is optionally substituted, and the substituent(s) can be one or more selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, heterocyclyl, or any combination thereof.
In an embodiment of the present disclosure, the ALK-TKIs represents the compound moiety represented by the following general formula:

wherein, R represents an alkyl group or H. In a sub-embodiment of the present disclosure, R represents a linear or branched C_1-10 alkyl group. In a further sub-embodiment of the present disclosure, the C_1-10 alkyl group is preferably a C_1-9 alkyl group, more preferably a C_1-8 alkyl group, still more preferably a C_2-8 alkyl group, and more preferably a C_1-7 alkyl group, even more preferably C_1-6 alkyl, C_1-5 alkyl, or C_1-4 alkyl. Representive examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and tert-pentyl.
In an embodiment of the present disclosure, the ULM represents a structure represented by the following formula (II):
wherein X represents CH₂ or C(O), Y represents CH₂, NH or O, and Z represents a carbonyl group (i.e., C(O)) or is absent.
In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents C(O), Y represents N-, and Z is absent.
In a sub-embodiment of the present disclosure, in the structure of the formula (II), X represents C(O), Y represents NH, and Z represents a carbonyl group.
In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents NH, and Z is absent.
In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents NH, and Z represents a carbonyl group.
In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents C(O), Y represents O, and Z is absent.
In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents O, and Z is absent.
In a sub-embodiment of the present disclosure, in the structure of the formula (II), X represents C(O), Y represents O, and Z represents a carbonyl group.
In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents O, and Z represents a carbonyl group.
In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents CH₂, and Z is absent.
In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents CH₂, Y represents CH₂, and Z represents a carbonyl group.
In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents C(O), Y represents CH₂, and Z is absent.
In a sub-embodiment of the present disclosure, in the structure of formula (II), X represents C(O), Y represents CH₂, and Z represents a carbonyl group.
In an embodiment of the present disclosure, the ULM represents a structure represented by the following formula (III):
wherein Z represents a carbonyl group or is absent.
In an embodiment of the present disclosure, the LIN represents: a linear or branched C₁-C₂₀ alkylene chain; -(CH₂)_n1-(O(CH₂)_n2)_m1-; -(CH₂)_n1-(O(CH₂)_n2)_m1-O-(CH₂)_n3-; -(CR₁R₂)_n1-(O(CR₁R₂)_n2)_m1-O-(CR₁R₂)_n3-; -(CH₂)_n1-(C(O)NH-(CH₂)_n2)_m1-; -(CH₂)_n1-(C(O)NH-(CH₂)_n2)_m1-(CH₂)_n3-; -(CH₂)_n1-(O(CH₂)_n2)_m1-O-(CH₂)_n3-C(O)NH-(CH₂)_n4-(O(CH₂)_n5)_m2-O-(CH₂)_n6-;-(CR₁R₂)_n1-(O(CR₁R₂)_n2)_m1-O-(CR₁R₂)_n3-C(O)NH-(CR₁R₂)_n4-(O(CR₁R₂)_n5)_m2-O-(CR₁R₂)_n6-; -(CH₂)n₁-C(O)NH-(O(CR₁R₂)_n2)_m1-; a linear or branched alkylene chain interrupted one or more times by one or more selected from the group consisting of NHC(O), NHC(O)NH, S, sulfinyl, sulfonyl, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, or heteroarylene, or any combination thereof; or -(CH₂)_n1-(O(CH₂)_n2)_m1- in which alkylene carbon chain is interrupted one or more times by one or more selected from the group consisting of arylene, heterocyclylene, heteroarylene group or any combination thereof;
wherein R₁ and R₂ each independently represent a linear or branched C₁-C₁₀ alkyl group or a cycloalkyl group; and
n1, n2, n3, n4, n5, n6, m1, and m2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN represents:

-(CH₂)₂O(CH₂)₂OCH₂-; -CH₂O(CH₂)₂OCH₂-; - (CH₂)₃O(CH₂)₂-;
- (CH₂)₃O(CH₂)₂O(CH₂)₂-; -(CH₂)₃O(CH₂)₃-; -(CH₂)₂O(CH₂)₂-;
-(CH₂)₂O(CH₂)₂O(CH₂)₂-; -(CH₂)₂O(CH₂)₂O(CH₂)₂-;
-(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂-; -(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₃-;
-(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂-;
-(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂-;
-(CH₂)₃O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂-; or
-(CH₂)₃O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₃-.

In an embodiment of the present disclosure, the LIN represents: -CH₂-; -(CH₂)₂-; -(CH₂)₃-; -(CH₂)₄-; -(CH₂)₅-; -(CH₂)₆-; -(CH₂)₇-; -(CH₂)₈-; -(CH₂)₉-; -(CH₂)₁₀-;-(CH₂)₁₁-; -(CH₂)₁₂-; -(CH₂)₁₃-; -(CH₂)₁₄-; -(CH₂)₁₅-; -(CH₂)₁₆-; -(CH₂)₁₇-; -(CH₂)₁₈-; -(CH₂)₁₉-; or -(CH₂)₂₀-.
In an embodiment of the present disclosure, the linear or branched alkylene chain is substituted one or more times with one or more substituents selected from the group consisting of hydroxyl, amino, mercapto, or halogen.
In an embodiment of the present disclosure, the LIN represents a linear or branched C₁-C₂₀ alkylene chain substituted with one or more substituents selected from the group consisting of hydroxyl, amino, mercapto, halogen, or any combination thereof. In a sub-embodiment of the present disclosure, the number of the substituent may be, for example, 1-20, or 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4. , 1-3, 1-2 or 1.
In an embodiment of the present disclosure, the LIN represents-(CH₂)₃CH(OH)CH(OH)(CH₂)₄-.
In an embodiment of the present disclosure, the LIN represents: -(CH₂)_n1-triazolylene-(CH₂)_n2-; -(CH₂)_n1-(O(CH₂)_n2)_m1-O-(CH₂)_n3-triazolylene-(CH₂)_n4-(O(CH₂)_n5)_m2-O-(CH2)_n6-;-(CH2)n₁-triazolylene-(CH₂)_n2-(O(CH₂)_n3)m₁-O-(CH₂)_n4-; or -(CH₂)n_1-(O(CH₂)_n2)_m1-O-(CH₂)_n3-triazolylene-(CH₂)_n4-; and
n1, n2, n3, n4, n5, n6, m1, and m2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN represents:
In an embodiment of the present disclosure, the LIN represents:
-(CH₂)₂C(O)NH(CH₂)₂-; -(CH₂)₃C(O)NH(CH₂)₃-; -(CH₂)₃C(O)NH(CH₂)₄-; - (CH₂)₆C(O)NH (CH₂)₇-; or -(CH₂)₈C(O)NH(CH₂)₈-.
In an embodiment of the present disclosure, the LIN is -(CH₂)_n1-NHC(O)-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN is -(CH₂)₃NHC(O)(CH₂)₃-.
In an embodiment of the present disclosure, the LIN is -(CH₂)_n1-NHC(O)NH-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN is -(CH₂)₄NHC(O)NH(CH₂)₄-.
In an embodiment of the present disclosure, the LIN is -(CH₂)_n1-S-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN represents: -(CH₂)₅S(CH₂)₅- or-(CH₂)₆S(CH₂)₅-.
In an embodiment of the present disclosure, the LIN is -(CH₂)_n1-S(O)-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN represents: -(CH₂)₅S(O)(CH₂)₅- or-(CH₂)₆S(O)(CH₂)₅-.
In an embodiment of the present disclosure, the LIN is -(CH₂)_n1-S(O)₂-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN represents: -(CH₂)₅S(O)₂(CH₂)₅- or-(CH₂)₆S(O)₂(CH₂)₅-.
In an embodiment of the present disclosure, the LIN is -(CH₂)_n1-CH=CH-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN is -(CH₂)₄CH=CH(CH₂)₃-.
In an embodiment of the present disclosure, the LIN is -(CH₂)_n1-C=C-(CH₂)_n2- or -(CH₂)_n1-C=C-C=C-(CH₂)_n2-, wherein n1 and n2 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN represents -(CH₂)₂C≡C(CH₂)₂- or-(CH₂)_SC≡C(CH₂)₄-.
In an embodiment of the present disclosure, the LIN represents a linear or branched alkylene chains interrupted one or more times by one or more selected from the group consisting of NHC(O), NHC(O)NH, S, sulfinyl, sulfonyl, alkynylene, alkenylene, spiro-cycloalkylene, arylene, heterocyclylene, heteroarylene group, or any combination thereof.
In an embodiment of the present disclosure, the LIN represents -(CH₂)_n1-piperazinylene-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN represents -CH₂-piperazinylene-CH₂-,-(CH₂)₂-piperazinylene-(CH₂)₂-, -(CH₂)₃-piperazinylene-(CH₂)₃-, -(CH₂)₂-piperazinylene-(CH₂)₃-, -CH₂-piperazinylene-(CH₂)₂-, -CH₂-piperazinylene-(CH₂)₃-, or-(CH₂)₂-piperazinylene-(CH₂)₃-.
In an embodiment of the present disclosure, the LIN represents -(CH₂)_n1-phenylene-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
In an embodiment of the present disclosure, the LIN represents -CH₂-phenylene-CH₂-,-(CH₂)₂-phenylene-(CH₂)₂-, -CH₂-phenylene-(CH₂)₂-, -(CH₂)₂-phenylene-CH₂-, -(CH₂)₃-phenylene-(CH₂)₃-, -CH₂-phenylene-(CH₂)₃-, -(CH₂)₂-Phenylene-(CH₂)₃-, -(CH₂)₃-phenylene-(CH₂)₂-, or -(CH₂)₃-phenylene-CH₂-.
In an embodiment of the present disclosure, the LIN represents a 1,4-piperazinylene, a spiro-cycloalkylene, or a 1,3-dialkynylene group, wherein when LIN is a 1,4-piperazinylene, the group A of the compound of formula (I) is a carbonyl group.
In an embodiment of the present disclosure, the LIN represents
or
wherein when the LIN is a 1,4-piperazinylene, the group A of the compound of the formula (I) is a carbonyl group.
In an embodiment of the present disclosure, the LIN represents a spiro-cycloalkylene, and the spiro-cycloalkylene may be a spiro[3.3]heptanylene (for example
), spiro[4.5]decanylene, spiro[5.5]undecanylene, or 4-methylspiro[2.4]heptanylene.
In an embodiment of the present disclosure, the LIN represents:
and the group A is C(O).

Particularly preferred are the following compounds of formula I and their salts (especially pharmaceutically acceptable salts) in Tables 1 and 2 of the present disclosure:

Table 1. Structural formulas and names of the compounds of the present disclosure

Table 2. Structural formulas and names of the compounds of the present disclosure

It should be recognized that the compounds of formula (I) of the present disclosure may have a stereo configuration and can therefore exist in more than one stereoisomer form. The disclosure also relates to compounds of formula (I) having a stereo configuration in pure or substantially pure isomeric form, e.g., greater than about 90% enantiomeric/diastereomeric excess ("ee"), such as greater than about 95% ee or 97% ee, or greater than about 99% ee, and mixtures thereof, including racemic mixtures. The purification of said isomers and the separation of said isomeric mixtures may be achieved by standard techniques known in the art (e.g., asymmetric synthesis (for example, by using chiral intermediates) and/or chiral resolution and the like).
The present disclosure also provides a pharmaceutical composition comprising, as an active ingredient, the compound of formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The pharmaceutical composition of the present disclosure further includes at least one additional medicine for treating or preventing cancer.
In another aspect of the present disclosure, the compound of formula (I) according to the disclosure, or a pharmaceutically acceptable salt thereof, is for use as a medicament.
In another aspect of the present disclosure, the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, is used for preventing and/or treating cancer.
Cancers include but are not limited to lung cancer, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer, ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, EGFR-mutated non-small cell lung cancer; Lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma (ALCL), diffused large B-cell lymphoma; inflammatory myofibroblastic tumor (IMT); colorectal cancer; brain tumor, glioma, glioblastoma; Acute myeloid leukemia (AML); and ovarian cancer etc.
In one embodiment of the present disclosure, the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, is used for preventing and/or treating lung cancer.
In one embodiment of the present disclosure, the lung cancer is e.g., selected from the group consisting of non-small cell lung cancer (NSCLC) such as anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer.
Another aspect of the present disclosure provides the use of the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of cancer.
In one embodiment of the use of compound of formula (I) of the the present disclosure, the cancers include but are not limited to lung cancer, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer, ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, EGFR-mutated non-small cell lung cancer; Lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma (ALCL), diffused large B-cell lymphoma; inflammatory myofibroblastic tumor (IMT); colorectal cancer; brain tumor, glioma, glioblastoma; Acute myeloid leukemia (AML); and ovarian cancer etc.
In one embodiment, the lung cancer is e.g., selected from the group consisting of non-small cell lung cancer (NSCLC) such as anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer.
A further aspect of the present disclosure also provides a method for treating or preventing cancer, which comprises administering to a subject a therapeutically effective amount of the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
In the method for treating or preventing cancer according to the present disclosure, the compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the subject by at least one mode of administration selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, Pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous administration.
In one embodiment of the method for treating or preventing cancer according to the present disclosure, the cancers include but are not limited to lung cancer, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer, ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, EGFR-mutated non-small cell lung cancer; Lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma (ALCL), diffused large B-cell lymphoma; inflammatory myofibroblastic tumor (IMT); colorectal cancer; brain tumor, glioma, glioblastoma; Acute myeloid leukemia (AML); and ovarian cancer etc.
In one embodiment of the method for treating or preventing cancer according to the present disclosure, the lung cancer is e.g., selected from the group consisting of non-small cell lung cancer (NSCLC) such as anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer.

Definition

Herein, the compound of the formula (I) of the present disclosure is also referred to as a PROTAD (small) molecule, a PROTAD comppound as an ALK protein degradation agent, a PROTAD compound, a degradation agent, ALK PROTAD (compound(s)) or an ALK protein modulator, which can be used interchangeably.
Herein, the structure represented by formula (Ia) as described above is a monovalent chemical moiety formed or derived from Crizotinib by removing a single hydrogen atom on the nitrogen of piperidinyl. The structure represented by formula (Ib) as described above is a monovalent chemical moiety derived from Ceritinib by removing a single hydrogen atom on the nitrogen of piperidinyl.
Herein, the structures represented by formulae (Ic), (Id), and (Ie) as described above are all analogs of Alectinib.
Herein, the structures represented by the formulas (If), (Ig), and (Ih) as described above are all analogs of Brigatinib.
Herein, the structure represented by the formula (Ii) is a monovalent chemical moiety derived from TAE684 (NVP-TAE684) by removing the methyl group on the nitrogen of piperazinyl.
Herein, the structure represented by the formula (Ij) is a monovalent chemical moiety derived from ASP3026 by removing the methyl group on the nitrogen of piperazinyl.
Herein, the structure represented by formula (Ik) is a monovalent chemical moiety derived from GSK1838705A by removing one or two methyl groups on the dimethylamino group.
Herein, the structure represented by the formula (Il) is a monovalent chemical moiety derived from AZD3463 by removing a single hydrogen atom from the primary amine group (-NH₂).
Herein, the structure represented by formula (Im) is a monovalent chemical moiety derived from Entrectinib (RXDX-101) by removing the methyl group on the nitrogen of piperazinyl.
Herein, the structure represented by formula (In) is a monovalent chemical moiety derived from Ensartinib (X-396) by removing a single hydrogen atom on the nitrogen of piperazinyl.
Herein, a bond interrupted by a wavy line shows the point of attachment of the radical depicted. For example, the group depicted below
is the chemical moiety represented by formula (Ia), which is connected to the rest part of the compound of formula (I) through the N atom of piperidinyl.
Herein, the ULM can represents a structure of the following formula (II)
wherein X represents CH₂ or C(O), Y represents CH₂, NH or O, and Z represents a carbonyl group or is absent. The structure of formula (II) is a derivative of Thalidomide, Lenalidomide, or Pomalidomide.
Herein, the ULM can also represents a structure of the following formula (III)
where Z represents a carbonyl group or is absent. The structure of formula (III) is a derivative of VHL-1.
As used herein, the terms "LIN" and "linker" are used interchangeably and both refers to a linking group in a compound of formula (I).
As used herein, the term "intermediate LM" refers to an intermediate compound in the following schemes for synthesizing the target compounds of the present disclosure by reacting with ALK-TKIs, for example, Brigatinib derivatives, Erlotinib derivatives, Ceritinib, or Crizotinib derivatives.
As used herein, the term "halogen atom" or "halogen" used alone or in combination refers to fluorine, chlorine, bromine or iodine, and is preferably F, Cl or Br.
As used herein, the term "alkyl" used alone or in combination refers to a linear or branched alkyl group. The term "(C_x-C_y) alkyl" or "C_x-y alkyl" (x and y are each an integer) refers to a linear or branched chain alkyl group containing x to y carbon atoms. The term "C_1-10 alkyl" used alone or in combination in the present disclosure refers to a linear or branched chain alkyl group containing 1 to 10 carbon atoms. The C_1-10 alkyl group of the present disclosureis preferably a C_1-9 alkyl group, or a C_1-8 alkyl group, or a C_2-8 alkyl group, or a C_1-7 alkyl group, or a C_1-6 alkyl, C_1-5 alkyl, or C_1-4 alkyl. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl and decyl. The term "C_1-3 alkyl group" in the present disclosure refers to an alkyl group containing 1 to 3 carbon atoms, and its representative examples include methyl, ethyl, n-propyl, and isopropyl.
As used herein, the "alkyl" is optionally substituted, and the substituent can be one or more selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, heterocyclyl, or any combination thereof.
As used herein, the term "alkylene" (which is used interchangeably with "alkylene chain") used alone or in combination refers to a linear or branched divalent saturated hydrocarbon group composed of carbon and hydrogen atoms. The term "C_x-C_y alkylene" or "C_x-y alkylene" (x and y are each an integer) refers to a linear or branched alkylene group containing from x to y carbon atoms. The C₁-c₃₀ alkylene group in the present disclosure is preferably C₁-C₂₉ alkylene, C₁-C₂₈ alkylene, C₁-C₂₇ alkylene, C₁-C₂₆ alkylene, C₁-C₂₅ alkylene, C₁-C₂₄ alkylene, C₁-C₂₃ alkylene, C₁-C₂₂ alkylene, C₁-C₂₁ alkylene, C₁-C₂₀ alkylene, C₁-C₁₉ alkylene, C₁-C₁₈ alkylene, C₁-C₁₇ alkylene, C₁-C₁₆ alkylene, C₁-C₁₅ alkylene, C₁-C₁₄ alkylene, C₁-C₁₃ alkylene, C₁-C₁₂ alkylene, C₁-C₁₁ alkylene, C₁-C₁₀ alkylene , C₁-C₉ alkylene, C₁-C₈ alkylene, C₁-C₇ alkylene, C₁-C₆ alkylene, C₁-C₅ alkylene, C₁-C₄ alkylene, C₁-C₃ alkylene, or C₁-C₂ alkylene. Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene , neopentylene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, peptacosylene, octacosylene, nonacosylene, and triacontylene.
As used herein, the term "aryl" used alone or in combination refers to an aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally one or more fused rings, such as phenyl or naphthyl or fluorenyl . In the present disclosure, the "aryl" is an optionally substituted aryl. A substituted aryl refers to an aryl group optionally substituted 1-3 times with a substituent(s) selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, halogen, amino, or hydroxyl.
As used herein, the term "arylene" used alone or in combination refers to a divalent aromatic hydrocarbon group containing from 5 to 14 carbon atoms and optionally one or more fused rings, such as phenylene group, naphthylene group or fluorenylene group. In the present disclosure, the "arylene" is an optionally substituted arylene. A substituted arylene group refers to an arylene group optionally substituted 1-3 times with a substituent(s) selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, halogen, amino, or hydroxyl.
As used herein, the term "C_1-3 alkoxy group" used alone or in combination refers to a linear or branched alkoxy group containing from 1 to 3 carbon atoms. Representative examples of C_1-3 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. Preferred are methoxy and ethoxy.
As used herein, the term "cycloalkyl" used alone or in combination refers to a saturated or partially unsaturated (e.g., containing one or more double bonds, but not having a completely conjugated π-electron system) monovalent monocyclic or bicyclic cyclic hydrocarbon radical having from 3 to 12 carbon atoms. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, and spiro-cycloalkyl..
As used herein, the term "cycloalkylene", used alone or in combination, refers to a saturated and partially unsaturated (e.g., containing one or more double bonds, but not having a fully conjugated π-electron system) divalent monocyclic or bicyclic cyclic hydrocarbon group having from 3 to 12 carbon atoms. Representative examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, and spiro-cycloalkylene..
As used herein, the term "heteroaryl" used alone or in combination refers to a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one or more (eg, from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Representative examples of such heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-a]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, 4H-fluoro[3,2-b]pyrrolyl, pyrrolo[2,1-b]thiazolyl and imidazo[2,1-b]thiazolyl. According to a clear definition, heteroaryl groups may be unsubstituted or substituted. A substituted heteroaryl group refers to a heteroaryl group optionally substituted 1-3 times with a substituent(s)preferably selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, or hydroxyl.
As used herein, the term "heteroarylene" used alone or in combination refers to a 5- to 10-membered monocyclic or bicyclic divalent aromatic ring group containing one or more (eg, from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Representative examples of such heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzoisoxazolylene, benzothiazolylene, benzoisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolylene, isoquinolylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo[1,5-a]pyridinylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2-a]pyridinylene, 1H-pyrrolo[3,2-b]pyridinylene, 1H-pyrrolo[2,3-b]pyridinylene, 4H-fluoro[3,2-b]pyrrolylene, pyrrolo[2,1-b]thiazolylene, and imidazo[2,1-b]thiazolylene. According to a clear definition, the heteroarylene group may be unsubstituted or substituted. A substituted heteroarylene group refers to a heteroarylene group optionally substituted 1-3 times by a substituent(s)preferably selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, or hydroxyl.
As used herein, the term "heterocyclyl" used alone or in combination refers to a 4- to 6-membered saturated monocyclic monovalent cyclic hydrocarbon group containing one or more heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Examples of the heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, triazolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and dioxanyl. The heterocyclyl may be unsubstituted or substituted as explicitly defined. A substituted heterocyclyl group refers to a heterocyclyl group optionally substituted 1-3 times with a substituent(s)preferably selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, or hydroxy.
As used herein, the term "heterocyclylene" used alone or in combination refers to a 4- to 6-membered saturated monocyclic divalent cyclic hydrocarbon group containing one or more heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Examples of the heterocyclylene group include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, triazolylend, tetrahydrofuranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, and dioxanylene. The heterocyclylene group may be unsubstituted or substituted as explicitly defined. A substituted heterocycloalkylene refers to a heterocycloalkylene group optionally substituted 1-3 times by a substituent(s) preferably selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, cyano, trifluoromethyl , heterocyclyl, halogen, amino, or hydroxyl.
As used herein, the term "spiro-cycloalkylene" used alone or in combination refers to a divalent alicyclic hydrocarbon group derived by removing two hydrogen atoms from any one or two free valence carbon atom(s) of the alicyclic hydrocarbon group in which two rings share one common carbon atom. Representative examples include, but are not limited to, spiro[3.3]heptanylene (for example
), spiro[4.5]decanylene, spiro[5.5]undecanylene, 4-methylspiro[2.4] heptanylene etc.
As used herein, the term "alkynyl" used alone or in combination refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4) carbon atoms. Examples of the alkynyl include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1,3-dialkynyl.
As used herein, the term "alkynylene" used alone or in combination refers to a linear or branched divalent hydrocarbon group containing one or more carbon-carbon triple bonds and containing from 2 to 10 (e.g., from 2 to 6, or from2 to 4) carbon atoms. Examples of the alkynylene group include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.
As used herein, the term "alkenyl" used alone or in combination refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4) carbon atoms. Examples of the alkenyl group include, but are not limited to, vinyl, 1-propenyl, and 1-butenyl.
As used herein, the term "alkenylene" used alone or in combination refers to a linear or branched divalent hydrocarbon group containing one or more carbon-carbon double bonds and containing from 2 to 10 (e.g., from 2 to 6, or from 2 to 4) carbon atoms. Examples of the alkenylene group include, but are not limited to, vinylidene (e.g., -CH=CH-), 1-propenylene, and 1-butenylene.
Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of formula I according to the disclosure are also encompassed within the scope of the invention.
In all embodiments of the disclosure, the salt or pharmaceutically acceptable salt of the compound of formula I refers to a non-toxic inorganic or organic acid and/or base addition salt. Examples include, but are not limited to, sulfate, hydrochloride, citrate, maleate, sulfonate, or p-toluenesulfonate etc.
"Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, with which the useful compounds according to the present disclosure are carried or transported into or administered to a patient so that they can perform their intended function. Generally, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in the present disclosure, and is not harmful to the patient, and the carrier must be "acceptable." Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; and other common non-toxic compatible substances used in pharmaceutical preparations.
A "therapeutically effective amount" of a compound of the disclosure depends on the age, sex, and weight of the patient, the patient's current medical condition, and the cancer progression of the patient being treated. Those skilled in the art will be able to determine a suitable dosage based on these and other factors.
The term "room temperature" used herein refers to the ambient temperature, such as a temperature of 20-30 °C.
The compound developed by the present invention belongs to a specific protein-degrading agent, which is composed of three parts: a target protein anchoring part, a protein degradation system (such as an E3 ligase) recruitment part, and a linker. In the present disclosure, an inhibitor targeting ALK protein is selected as an anchoring part, and an E3 ligase ligand is combined with an ALK protein inhibitor through a linker to develop a degradation agent targeting ALK protein. Through the specific recognition of target proteins by ALK-TKIs, the phosphorylation of ALK protein is inhibited, and at the same time, E3 ligase specifically ubiquitinates ALK protein to achieve degradation and elimination, and finally can remove the target protein from tumor cells. Because ALK mutation-positive lung cancer cells are highly dependent on the presence and activity of ALK protein, completely degrading ALK protein and inhibiting residual ALK activity can not only inhibit tumorigenesis and progression, but also potentially overcome resistance to targeted drugs. In addition, the degrading agent designed and developed by the present invention can also target and inhibit other tyrosine kinase receptors including ROS1, c-MET, insulin receptor, IGFIR and EGFR with lung cancer drivering mutation, etc. The compounds developed by the present invention provide potentially alternative treatments for cancers that are positive for these targets. This research will provide a new treatment strategy for lung cancer patients in the context of precision medicine.

Examples

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. The invention may be practiced without some or all of these specific details. In other cases, well-known process operations have not been described in detail in order not to unnecessarily obscure the present invention. Although the present invention will be described in conjunction with specific embodiments, it should be understood that this is not intended to limit the present invention to these embodiments.
The following abbreviations are used throughout the description and examples:

Boc: Tert-butoxycarbonyl
Con.: concentration
DCM: Dichloromethane
DMF: N, N-dimethylformamide
DMSO: Dimethyl sulfoxide
DIPEA: N, N-diisopropylethylamine
EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
ESI: Electrospray ionization
equiv: equivalent
EtOH: Ethanol
HOAT: 1-hydroxy-7-azobenzotriazole
HPLC: High performance liquid chromatography
HRMS: High resolution mass spectrometry
LC-MS: Liquid chromatography-mass spectrometry
LRMS: Low resolution mass spectrometry
LC: Liquid chromatography
Me: methyl
MeCN: Acetonitrile
MeOH: Methanol
MS: Mass spectrometry
MW: microwave
NMM: N-methylmorpholine
NMP: N-methylpyrrolidone
¹H NMR: Proton nuclear magnetic resonance
rt: Room temperature
TFA: Trifluoroacetate
TLC: Thin layer chromatography
TMS: Trimethylsilyl
Xantphos; or X-Phos: 4,5-bis (diphenylphosphine)-9,9-dimethylxanthene

In the present disclosure, the ¹H NMR spectrum is measured using a Bruker-500MHz nuclear magnetic resonance instrument, and CD₃OD containing 0.1% TMS is used as a solvent, wherein the ¹H NMR spectrum uses CD3OD (δ = 3.31 ppm) as an internal standard; or CDCl₃ containing 0.1% TMS is used as the solvent, wherein the ¹H NMR spectrum uses CDCl₃ (δ = 7.26 ppm) as the internal standard; or DMSO-d ₆ containing 0.03% TMS as the solvent, wherein the ¹H NMR spectrum uses DMSO-d ₆ (δ = 2.50 ppm) as the internal standard; LRMS spectrum was measured on an AB Triple 4600 mass spectrometer, HPLC preparation was measured on a SHIMADZU LC-20AP type instrument, and HPLC purity was measured on a SHIMADZU LC-30AP or Waters 1525 type instrument. All reactions were performed in the air without special instructions; the reactions were followed by TLC or LC-MS.
Solvents and reagents are processed as follows:

The solvents used in the reaction: DCM, DMF, anhydrous EtOH, and anhydrous MeOH were purchased from Chinese Sinopharm Group;
Preparative grade CH₃CN and deionized water are used in HPLC preparation;
Unless otherwise stated, Alectinib, Alectinib analogue A, Crizotinib, Ceritinib, Brigatinib, TAE684 (NVP-TAE684), ASP3026, GSK1838705A, AZD3463, Entrectinib (RXDX- 101), Ensartinib (X-396)) and various kinds of carbon chain linking unit (linker group of the compound of the formula (I) of the present disclosure) can be directly purchased.

Other reagents and medicines were purchased from the manufacturer and used directly without special instructions.

General synthesis procedure

General synthesis procedure for Brigatinib analogue A, B, C (ALK inhibitors)

Wherein group X and Y are as shown in Scheme 1.

General synthesis procedure for Alectinib analogue B, C (ALK inhibitors):

Wherein group X and Y are as shown in Scheme 2.
In addition, the Alectinib amalogue A (9-ethyl-6,6-dimethyl-11-oxo-8- (piperazin-1-yl) - 6,11-dihydro- 5H-benzo[b]carbazole-3-carbonitrile) can also be purchased directly.

General synthesis procedure for intermediate LM (Pomalidomide PEG linker):

Wherein n is an interger of from 1 to 5, as shown in Scheme 3.

General synthesis procedure for intermediate LM (Pomalidomide alkyl carbon chain linker)

Wherein n is an interger of from 0 to 5, as shown in Scheme 4.

General synthesis procedure for intermediate LM (VHL-1 PEG linker):

Wherein n is an interger of from 0 to 10, as shown in Scheme 5.

General synthesis procedure for intermediate LM (VHL-1 alkyl carbon chain linker):

Wherein n is an interger of from 0 to 7, as shown in Scheme 6.

General synthesis procedure for intermediate LM (Lenalidomide carbonyl alkyl carbon chain linker):

Wherein n is an interger of from 1 to 5, as shown in Scheme 7.

General synthesis procedure for intermediate LM (Lenalidomide alkyl carbon chain linker)

Wherein n is an interger of from 1 to 20, as shown in Scheme 8.

General synthesis procedure for special intermediate LM (SIAIS151103):

General synthesis procedure for special intermediate LM (SIAIS164119):

General synthesis procedure for special intermediate LM (SIAIS164050):

General synthesis procedure for special intermediate LM (SIAIS164128):

General synthesis procedure for special intermediate LM (SIAIS219048):

Wherein n is 7, as shown in Scheme 13.

General synthesis procedure for special intermediate LM (SIAIS172147):

General synthesis procedure for compounds in this patent:

Intermediate Examples

Intermediate Example 1: synthesis of Brigatinib Analogue A(SIAIS1197135)

Brigatinib Analogue A(SIAIS1197135) was synthesized according to scheme 1.

Synthesis of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (SIAIS1197111):

To a solution of 5-fluoro-2-nitroanisole (7 g, 40.9 mmol) in DMF (60 mL) were added K₂CO₃ (8.4 g, 60.8 mmol) and tert-butyl piperazine-1-carboxylate (9.1 g, 48.9 mmol) at room temperature under air. After stirring at the same temperature overnight, the reaction mixture was quenched with water, extracted with ethyl acetate, washed with brine and dried over anhydrous Na₂SO₄. The solvent was evaporated under the reduced pressure and the residue was purified by recrystallization (eluent: petroleum ether / ethyl acetate = 5:1) to afford SIAIS1197111 in 80% yield (11.1 g) as a yellow solid. ¹H NMR (500 MHz, DMSO) δ 7.89 (d, J = 9.3 Hz, 1H), 6.57 (d, J = 9.5 Hz, 1H), 6.52 (s, 1H), 3.90 (s, 3 H), 3.46 (s, 8H),1.42 (s, 9H). HRMS (ESI) calcd for C₁₆H₂₄N₃O₅ ⁺ [M+H]⁺, 338.1710; found, 338.1610.

Synthesis of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (SIAIS1197129):

To a stirred solution of SIAIS1197111 (10 g, 29.6 mmol) in EtOH (90 mL) and H₂O (30 mL) were added NH₄Cl (6.3 g, 118.6 mmol) and Fe powder (8.3 g, 148.2 mmol). Then the resulting mixture was refluxed at 80 °C for 2 h under an atmosphere of nitrogen. When the reaction was complete, the crude mixture was cooled down to room temperature, filtered by silica, after solvent evaporation, extracted with DCM (3 x 50 mL), the combined organic layer was washed with brine (20 mL), then dried over Na₂SO₄ and concentrated in vacuum to afford SIAIS1197129 in 85% yield (7.7 g) as a gray solid. ¹H NMR (500 MHz, MeOD) δ 6.72 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.47 (d, J = 7.0 Hz, 1H), 3.86 (s, 3H), 3.57 (s, 4H), 2.99 (s, 4H), 1.50 (s, 9H). HRMS (ESI) calcd for C₁₆H₂₆N₃O₃ ⁺ [M+H]⁺, 308.1969; found, 308.1882.

Synthesis of (2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. (SIAIS1197135):

To a solution of 2,5-dichloro-N-(2-(dimethylphosphoryl)phenyl)pyrimidin-4-amine (2 g, 6.3 mmol) in DMF (30 mL) were added SIAIS1197129 (2.4 g, 7.8 mmol), Pd(OAc)₂ (176 mg, 0.78 mmol), Xantphos (810 mg, 1.4 mmol) and Cs₂CO₃(6.4 g, 19.6 mmol) in microwave tube, the solution was purged and refilled with nitrogen three times. Then the mixture was stirred at 110 °C for 2 h in the microwave. After the starting material was consumed, the reaction mixture was filtered through a pad of silica gel and most of the solvent of the filtrate was removed under the reduced pressure. Then the mixture was quenched with water, extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na₂SO₄. The solvent was evaporated under the reduced pressure and the residue was purified by reverse phase ISCO (C18) to give the title compound (900 mg) as a brown solid.
To a solution of above compound (900 mg) in DCM (6 mL) was added TFA (2 mL) under air. The resulting solution was stirred at room temperature for 1 h. Then most of the solvent was removed under the reduced pressure, the pH of the solution was adjusted to 8-9 with saturated NaHCO₃ solution, then extracted with DCM, dried over anhydrous Na₂SO₄. The solvent was evaporated under the reduced pressure and the residue was purified by reverse phase ISCO (C18), eluent (v/v): MeOH/water = 10% -100%, to afford SIAIS1197135 as a yellow solid (701 mg, 23% yield over two steps). ¹H NMR (500 MHz, MeOD) δ 8.32 (dd, J = 8.2, 4.4 Hz, 1H), 8.04 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.61 (dd, J= 14.1, 7.7 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.26 (t, J = 7.5, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.45 (dd, J = 8.8, 2.5 Hz, 1H), 3.86 (s, 3H), 3.24 - 3.17 (m, 4H), 3.17 - 3.11 (m, 4H), 1.83 (d, J = 13.5 Hz, 6H). HRMS (ESI) calcd for C₂₃H₂₉ClN₆O₂P⁺ [M+H]⁺, 487.1773; found, 487.1773.

Intermediate Example 2: synthesis of Brigatinib Analogue B

Brigatinib Analogue B was synthesized according to scheme 1, using similar procedures for the preparation of Brigatinib Analogue A in Intermediate Example 1, the synthesis data and structural characterization data are as follows:
tert-butyl (1-(3-methoxy-4-nitrophenyl)piperazine-4-yl) carbamate (SIAIS151054). (yellow solid, 1.81 g, 88%) ¹H NMR (500 MHz, CDCl₃) δ 7.99 (t, J = 8.9 Hz, 1H), 6.41 (dd, J = 9.4, 2.5 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H), 4.49 (s, 1H), 3.94 (s, 3H), 3.86 - 3.82 (m, 2H), 3.71 (s, 1H), 3.09 - 3.00 (m, 2H), 2.11 - 2.03 (m, 2H), 1.89 - 1.75 (m, 2H), 1.45 (s, 9H).
tert-butyl (1-(4-amino-3-methoxyphenyl)piperazine-4-yl)carbamate (SIAIS151062). (gray solid, 411.6 mg, 90%) ¹H NMR (500 MHz, DMSO) δ 6.82 (d, J = 7.6 Hz, 1H), 6.50 (d, J = 8.5 Hz, 1H), 6.48 (d, J = 2.5 Hz, 1H), 6.28 (dd, J = 8.4, 2.4 Hz, 1H), 4.20 (s, 2H), 3.73 (s, 3H), 3.33 - 3.26 (m, 3H), 2.56 - 2.50 (m, 2H), 1.77 (d, J = 11.4 Hz, 2H), 1.53 - 1.45 (m, 2H), 1.39 (s, 9H).
(2-((2-((4-(4-aminopiperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (SIAIS151101). (yellow solid, 330 mg, 33% yield over two steps) ¹H NMR (500 MHz, DMSO) δ 8.49 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.53 (ddd, J = 14.0, 7.7, 1.3 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.10 (t, J = 7.1 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 6.46 (dd, J = 8.7, 2.5 Hz, 1H), 3.75 (s, 3H), 3.65 - 3.61 (m, 2H), 2.78 - 2.67 (m, 3H), 1.82 - 1.79 (m, 2H), 1.78 (s, 3H), 1.75 (s, 3H), 1.42 - 1.34 (m, 2H). HRMS (ESI) calcd for C₂₄H₃₁ClN₆O₂P [M+H]⁺: 501.1913, found, 501.1900.

Intermediate Example 3: synthesis of Brigatinib Analogue C

Brigatinib Analogue C was synthesized according to scheme 1, using similar procedures for the preparation of Brigatinib Analogue A in Intermediate Example 1, the synthesis data and structural characterization data are as follows:
tert-butyl 4-(1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)piperazine-1-carboxylate (SIAIS151059). (yellow solid, 1.02 g, 83%) ¹H NMR (500 MHz, MeOD) δ 7.93 (d, J = 9.4 Hz, 1H), 6.55 (dt, J = 13.4, 6.7 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 4.10 (s, 1H), 4.07 (s, 1H), 3.94 (d, J = 6.6 Hz, 3H), 3.43 (s, 4H), 3.02 - 2.93 (m, 2H), 2.60 - 2.55 (m, 5H), 2.02 - 1.95 (m, 2H), 1.57 (qd, J = 12.4, 4.0 Hz, 2H), 1.46 (s, 9H). HRMS (ESI) calcd for C₂₁H₃₃N₄O₅ [M+H]⁺: 421.2445, found, 421.2442.
tert-butyl 4-(1-(4-amino-3-methoxyphenyl)piperidine-4-yl)piperazine-1-carboxylate (SIAIS164003). (gray solid, 745 mg, 79%). ¹H NMR (500 MHz, MeOD) δ 6.59 (t, J = 56.8 Hz, 3H), 3.78 (s, 3H), 3.46 (s, 6H), 2.62 (d, J = 4.3 Hz, 6H), 2.42 (s, 1H), 1.98 (s, 2H), 1.69 (d, J = 9.7 Hz, 2H), 1.46 (s, 9H). HRMS (ESI) calcd for C₂₁H₃₅N₄O₃ [M+H]⁺: 391.2704, found, 391.3048.
(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino) pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. (SIAIS164005). (yellow solid, 350 mg, 37% yield over two steps). ¹H NMR (500 MHz, MeOD) δ 8.33 (dd, J = 8.2, 4.4 Hz, 1H), 8.03 (s, 1H), 7.69 - 7.64 (m, 1H), 7.60 (ddd, J = 14.0, 7.7, 1.4 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.26 (td, J = 7.6, 1.2 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.45 (dd, J = 8.8, 2.5 Hz, 1H), 3.85 (s, 3H), 3.73 - 3.63 (m, 2H), 3.11 - 3.02 (m, 4H), 2.79 - 2.66 (m, 6H), 2.48-2.43 (m, 1H), 1.99 (d, J = 12.5 Hz, 2H), 1.84 (d, J = 13.5 Hz, 6H), 1.72-1.63 (m, 2H). HRMS (ESI) calcd for C₂₈H₃₈ClN₇O₂P [M+H]⁺: 570.2508, found, 570.2498.

Intermediate Example 4: synthesis of Alectinib Analogue B (SIAIS184193)

Alectinib Analogue B 8-(4-aminopiperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (SIAIS184193) was synthesized according to scheme 2:
At room temperature, 9-ethyl-8-iodo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (440 mg, 1 mmol), 4-tert-butoxycarbonylaminopiperidine (377 mg, 1.4 mmol), Pd₂(dba)₃ (45.8 mg, 0.05 mmol), Sphos (82.1 mg, 0.2 mmol) anad dioxane (10 mL) was added sequentially in a 25 mL egg-shaped flask, the mixture was evacuated and replaced with argon, then NaHMDS (4 mL, 4 mmol, 1.0 M in THF) was added, the mixture was heated to 60 °C and stirred for 5 h. When the reaction was complete detected by TLC, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluent: hexanes/EA = 1:1) to give a brown solid.
To a solution of above brown solid (350 mg) in DCM (6 mL) was added TFA (2 mL) under air. The resulting solution was stirred at room temperature for 1 h. Then most of the solvent was removed under the reduced pressure, the pH of the solution was adjusted to 8-9 with saturated NaHCO₃ solution, extracted with DCM, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase ISCO (C18), eluent (v/v): MeOH/water = 10% -100%, to afford the desired product SIAIS184193 as yellow solid (310 mg, 60% over 2 steps). ¹H NMR (500 MHz, DMSO) δ 12.91 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.17 (d, J = 4.2 Hz, 2H), 8.05 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.61 (dd, J = 8.1, 1.3 Hz, 1H), 7.38 (s, 1H), 3.22 (d, J = 12.2 Hz, 3H), 2.86 (t, J = 11.4 Hz, 2H), 2.70 (q, J = 7.5 Hz, 2H), 2.06 (d, J = 10.0 Hz, 2H), 1.81 - 1.73 (m, 8H), 1.28 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₂₆H₂₉N₄O [M+H]⁺: 413.2336, found 413.2339.

Intermediate Example 5: synthesis of Alectinib Analogue C

Alectinib Analogue C was synthesized according to scheme 2, using similar procedures for the preparation of Alectinib Analogue B in Intermediate Example 4, the structural characterization data are as follows:
9-ethyl-6,6-dimethyl-11-oxo-8-(4-(piperazin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo [b]carbazole-3-carbonitrile. (SIAIS184192). (yellow solid, 280 mg, 48%) ¹H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 3.94 (s, 8H), 3.61 (s, 1H), 3.49 - 3.29 (m, 4H), 2.70 (q, J = 7.8 Hz, 2H), 1.76 (s, 6H), 1.61 (s, 4H), 1.28 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₃₀H₃₆N₅O [M+H]⁺: 482.2914, found 482.2911.

Intermediate Example 6: synthesis of 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid (SIAIS151001)

According to Scheme 3, a solution of 2-(2,6-dioxopipeiidin-3-yl)-4-fluoroisoindolin-1,3-dione (5 mmol, 1 equiv), tert-butyl 3-(2-aminoethoxy)propionate (6 mmol, 1.2 equiv) and DIPEA (25 mmol, 5 equiv) in NMP (8 mL) was stirred in a 30 mL microwave tube for 10 min at room temperature, then charged with argon and heated to 110 °C in a microwave reactor for 2 h. After cooling to RT, the reaction mixture was poured into 90% saline, extracted with EA(4 x 50 mL), the combined organic phase was washed with water (2 x 30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexanes/EA = 1:1) to give the desired tert-butyl ester intermediate. This intermediate was treated with 88% formic acid (20 mL) overnight at room temperature. After concentration under reduced pressure and freeze-drying, the desired product SIAIS151001 was obtained as yellow solid (1.0 g, 48% yield). ¹H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 11.09 (s, 1H), 7.57 (dd, J = 8.5, 7.5 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.59 (t, J = 5.7 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.65 (t, J = 6.3 Hz, 2H), 3.59 (t, J = 5.5 Hz, 2H), 3.46 (q, J = 5.5 Hz, 2H), 2.91 - 2.83 (m, 1H), 2.61 - 2.52 (m, 2H), 2.46 (t, J = 6.3 Hz, 2H), 2.05 - 2.00 (m, 1H);HRMS (ESI) calcd for C₁₈H₂₀N₃O₇ ⁺ [M + H]⁺ , 390.1301; found, 390.1261.

Intermediate Example 7: synthesis of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (SIAIS151004)

According to the procedures for the preparation of Intermediate Example 6, tert-Butyl 3-(2-(2-aminoethoxy)ethoxy)propanoate was used to prepare SIAIS151004 (yellow solid, 0.95 g, 51% yield). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.58 (dd, J = 8.0, 7.5 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 5.7 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.62 - 3.58 (m, 4H), 3.56 - 3.54 (m, 2H), 3.52 - 3.49 (m, 2H), 3.46 (dd, J = 11.1, 5.5 Hz, 2H), 2.92 - 2.84 (m, 1H), 2.66 - 2.51 (m, 2H), 2.42 (t, J = 6.4 Hz, 2H), 2.06 - 1.98 (m, 1H);HRMS (ESI) calcd for C₂₀H₂₄N₃O₈ ⁺ [M + H]⁺, 434.1558; found, 434.1445.

Intermediate Example 8: synthesis of 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (SIAIS151005)

According to the procedures for the preparation of Intermediate Example 6, tert-Butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate was used to prepare SIAIS151005 (yellow solid, 0.95 g, 61% yield). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.58 (dd, J = 8.0, 7.0 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.61 (t, J = 5.8 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.63 - 3.48 (m, 14H), 2.92 - 2.83 (m, 1H), 2.64 - 2.52 (m, 2H), 2.18 (t, J = 8.1 Hz, 2H), 2.07 - 1.99 (m, 1H). HRMS (ESI) calcd for C₂₂H₂₈N₃O₉ ⁺ [M + H]⁺, 478.1820; found, 478.1159.

Intermediate Example 9: synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (SIAIS151006)

According to the procedures for the preparation of Intermediate Example 6, tert-Butyl 1-amino-3,6,9,12-tetraoxapentadecan-15-oate was used to prepare SIAIS151006 (yellow solid, 0.87 g, 53% yield). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.58 (dd, J = 8.5, 7.5 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 5.7 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.63 - 3.48 (m, 18H), 2.92 - 2.84 (m, 1H), 2.63 - 2.52 (m, 2H), 2.41 (t, J= 6.4 Hz, 2H), 2.07 - 1.98 (m, 1H). HRMS (ESI) calcd for C₂₄H₃₂N₃O₁₀ ⁺ [M + H]⁺, 522.2082; found, 522.2178.

Intermediate Example 10: synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oic acid (SIAIS151007)

According to the procedures for the preparation of Intermediate Example 6, tert-Butyl 1-amino-3,6,9,12,15-pentaoxaoctadecan-18-oate was used to prepare SIAIS151007 (yellow solid, 0.8 g, 51% yield). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.58 (t, J= 8.0 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 5.7 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.63 - 3.54 (m, 8H), 3.54 - 3.48 (m, 12H), 3.30 (dd, J= 7.0 Hz, 4H), 2.92 - 2.84 (m, 1H), 2.63 - 2.52 (m, 2H), 2.06 - 1.99 (m, 1H). HRMS (ESI) calcd for C₂₆H₃₆N₃O₁₁ ⁺ [M + H]⁺ , 566.2344; found, 566.2679.

Intermediate Example 11: synthesis of (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (SIAIS151025)

According to Scheme 4, a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (7 mmol, 1 equiv), tert-butyl 3-(2-aminoethoxy)propionate (8.4 mmol, 1.2 equiv) and DIPEA (35 mmol, 5 equiv) in NMP (8 mL) was stirred in a microwave tube for 10 min at room temperature, then charged with argon and heated to 110 °C in a microwave reactor for 2 h. After cooling to RT, the reaction mixture was poured into 90% saline, extracted with ethyl acetate(4 x 50 mL), the combined organic phase was washed with water (2 x 30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent(v/v): hexanes/EA = 1:1) to give the desired tert-butyl ester intermediate. This intermediate was treated with 88% formic acid (20 mL) overnight at room temperature. After concentration under reduced pressure and freeze-drying, the desired product SIAIS151025 was obtained as yellow solid (1.2 g, 48% yield). ¹H NMR (500 MHz, DMSO) δ 11.10 (s, 1H), 7.59 (dd, J= 15.9, 8.5 Hz, 1H), 7.07 (d, J = 7.0 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.86 (t, J = 5.7 Hz, 1H), 5.06 (dt, J = 15.1, 7.6 Hz, 1H), 4.08 (d, J = 5.7 Hz, 2H), 2.92 - 2.84 (m, 1H), 2.63 - 2.52 (m, 2H), 2.07 - 2.02 (m, 1H). HRMS (ESI) calcd for C₁₈H₂₀N₃O₆ ⁺ [M + H]⁺, 332.0877; found, 332.0720.

Intermediate Example 12: synthesis of 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoic acid (SIAIS151026)

According to the procedures for the preparation of Intermediate Example 11, tert-Butyl 3-amino-propanoate was used to prepare SIAIS151026 (yellow solid, 0.93 g, 39% yield). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.59 (dd, J = 8.0, 7.5 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.67 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.53 (dd, J = 12.6, 6.3 Hz, 2H), 2.92 - 2.84 (m, 1H), 2.65 - 2.53 (m, 4H), 2.08 - 1.98 (m, 1H). HRMS (ESI) calcd for C₁₆H₁₆N₃O₆ ⁺ [M + H]⁺, 346.1034; found, 346.0868.

Intermediate Example 13: synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoic acid (SIAIS151019)

According to the procedures for the preparation of Intermediate Example 11, tert-Butyl 4-amino-butanoate was used to prepare SIAIS151019 (yellow solid, 0.8 g, 61% yield). ¹H NMR (500 MHz, DMSO) δ 12.14 (s, 1H), 11.09 (s, 1H), 7.58 (dd, J = 8.4, 7.3 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.65 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.32 (dd, J = 13.7, 6.7 Hz, 2H), 2.94 - 2.82 (m, 1H), 2.66 - 2.51 (m, 2H), 2.30 (t, J = 7.2 Hz, 2H), 2.05 - 2.00 (m, 1H), 1.82 - 1.75 (m, 2H). HRMS (ESI) calcd for C₁₇H₁₈N₃O₆ ⁺ [M + H]⁺, 360.1190; found, 360.1223.

Intermediate Example 14: synthesis of 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoic acid (SIAIS151020)

According to the procedures for the preparation of Intermediate Example 11, tert-Butyl 5-amino-pentanoate was used to prepare SIAIS151020 (yellow solid, 0.9 g, 50% yield). ¹H NMR (500 MHz, DMSO) δ 12.05 (s, 1H), 11.11 (s, 1H), 7.57 (dd, J = 8.3, 7.4 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.56 (t, J = 5.9 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 3.32 - 3.28 (m, 2H), 2.94 - 2.82 (m, 1H), 2.62 - 2.51 (m, 2H), 2.27 - 2.25 (m, 2H), 2.06 - 1.99 (m, 1H), 1.62 - 1.53 (m, 4H). HRMS (ESI) calcd for C₁₈H₂₀N₃O₆ ⁺ [M + H]⁺, 374.1347; found, 374.1384.

Intermediate Example 15: synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoic acid (SIAIS151027)

According to the procedures for the preparation of Intermediate Example 11, tert-Butyl 6-amino-hexanoate was used to prepare SIAIS151027 (yellow solid, 1.26 g, 61% yield). ¹H NMR (500 MHz, DMSO) δ 12.00 (s, 1H), 11.09 (s, 1H), 7.58 (dd, J = 8.3, 7.4 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.54 (t, J = 5.9 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.30 - 3.27 (m, 2H), 2.92 - 2.84 (m, 1H), 2.63 - 2.51 (m, 2H), 2.21 (t, J = 7.5 Hz, 2H), 2.08 - 1.98 (m, 1H), 1.60 - 1.50 (m, 4H), 1.38 - 1.31 (m, 2H). HRMS (ESI) calcd for C₁₉H₂₂N₃O₆ ⁺ [M + H]⁺ , 388.1503; found, 388.1119.

Intermediate Example 16: synthesis of 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoic acid (SIAIS151086)

According to the procedures for the preparation of Intermediate Example 11, tert-Butyl 7-amino-heptanoate was used to prepare SIAIS151086 (yellow solid, 1.3 g, 64% yield). ¹H NMR (500 MHz, DMSO) δ 12.04 (s, 1H), 11.09 (s, 1H), 7.58 (dd, J = 8.3, 7.3 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.53 (t, J = 5.9 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 3.28 (dd, J = 13.4, 6.7 Hz, 2H), 2.94 - 2.82 (m, 1H), 2.65 - 2.51 (m, 2H), 2.19 (t, J = 7.3 Hz, 2H), 2.05 - 2.00 (m, 1H), 1.60 - 1.53 (m, 2H), 1.53 - 1.46 (m, 2H), 1.37 - 1.28 (m, 4H). HRMS (ESI) calcd for C₂₀H₂₄N₃O₆ ⁺ [M + H]⁺ , 402.1660; found, 402.1643.

Intermediate Example 17: synthesis of 2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)acetic acid (SIAIS151010)

According to scheme 5, to a solution of diacid (2,2'-(ethane-1,2-diylbis(oxy))diacetic acid, 5.0 mmol, 2.5 equiv) in anhydrous DMF (10 mL) and anhydrous DCM (150 mL) was added NMM (10.0 mmol, 5 equiv), VHL-1 (2 mmol, 1 equiv), HOAt (2.4 mmol, 1.2 equiv) and EDCI (2.4 mmol, 1.2 equiv) at 0 °C. The resulting reaction solution was stirred at 0 °C for 5 h and then at room temperature overnight. After VHL-1 was totally consumed, the reaction was quenched with water (1 mL) and then concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1%TFA) = 10% -100%, to yield the desired product SIAIS151010 as white solid (0.2 g, 23%). ¹H NMR (500 MHz, DMSO) δ 8.98 (s, 1H), 8.60 (t, J = 5.9 Hz, 1H), 7.48 (d, J = 9.5 Hz, 1H), 7.40 (s, 4H), 4.57 (d, J = 9.6 Hz, 1H), 4.47 - 4.37 (m, 2H), 4.35 (s, 1H), 4.29 - 4.22 (m, 1H), 4.07 (d, J = 12.5 Hz, 1H), 3.97 (s, 2H), 3.69 - 3.59 (m, 8H), 2.44 (s, 3H), 2.07 - 2.03 (m, 1H), 1.93 - 1.87 (m, 1H), 0.94 (s, 9H). HRMS (ESI) calcd for C₂₈H₃₉N₄O₈S⁺ [M +H]⁺ , 591.2483; found, 591.2365.

Intermediate Example 18: synthesis of 3-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethoxy)propanoic acid (SIAIS151002)

According to the procedures for the preparation of Intermediate Example 17, 3,3'-(ethane-1,2-diylbis(oxy))dipropionic acid was used to prepare SIAIS151002 (white solid, 0.53 g, 44% yield). ¹H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 8.99 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 7.92 (d, J = 9.3 Hz, 1H), 7.41 (dd, J = 18.5, 8.2 Hz, 4H), 4.55 (d, J = 9.5 Hz, 1H), 4.46 - 4.40 (m, 2H), 4.36 (s, 1H), 4.23 (dd, J = 15.8, 5.4 Hz, 1H), 3.69 - 3.56 (m, 7H), 3.49 - 3.46 (m, 4H), 2.58 - 2.53 (m, 1H), 2.47 - 2.42 (m, 2H), 2.45 (s, 3H), 2.39 - 2.32 (m, 1H), 2.06 - 2.01 (m, 1H), 1.95 - 1.88 (m, 1H), 0.94 (s, 9H). HRMS (ESI) calcd for C₃₀H₄₃N₄O₈S⁺ [M +H]⁺ , 619.2796; found, 619.2973.

Intermediate Example 19: synthesis of (S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azaheptadecanoic acid (SIAIS151003)

According to the procedures for the preparation of Intermediate Example 17, 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))dipropionic acid was used to prepare SIAIS151003 (white solid, 0.63 g, 59% yield). ¹H NMR (500 MHz, DMSO) δ 8.99 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 7.92 (d, J = 9.4 Hz, 1H), 7.41 (dd, J = 18.5, 8.2 Hz, 4H), 4.56 (d, J = 9.4 Hz, 1H), 4.47 - 4.41 (m, 2H), 4.36 (s, 1H), 4.23 (dd, J = 15.9, 5.5 Hz, 1H), 3.70 - 3.57 (m, 8H), 3.51 - 3.47 (m, 7H), 2.58 - 2.52 (m, 1H), 2.47 - 2.42 (m, 2H), 2.45 (s, 3H), 2.39 - 2.32 (m, 1H), 2.08 - 2.00 (m, 1H), 1.94 - 1.88 (m, 1H), 0.94 (s, 9H). HRMS (ESI) calcd for C₃₂H₄₇N₄O₉S⁺ [M +H]⁺ , 663.3058; found, 663.3008.

Intermediate Example 20: synthesis of (S)-18-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)-19,19-dimethyl-16-oxo-4,7,10,13-tetraoxa-17-azaicosanoic acid (SIAIS151008)

According to the procedures for the preparation of Intermediate Example 17, 4,7,10,13-tetraoxahexadecanedioic acid was used to prepare SIAIS151008 (white solid, 0.53 g, 51% yield). ¹H NMR (500 MHz, DMSO) δ 8.98 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 7.91 (d, J = 9.4 Hz, 1H), 7.40 (dd, J = 18.8, 8.3 Hz, 4H), 4.55 (d, J = 9.4 Hz, 1H), 4.45 - 4.40 (m, 2H), 4.35 (s, 1H), 4.22 (dd, J = 15.8, 5.5 Hz, 1H), 3.69 - 3.54 (m, 10H), 3.48 (d, J = 2.7 Hz, 9H), 2.56 - 2.52 (m, 1H), 2.45 - 2.41 (m, 2H), 2.45 (s, 3H), 2.38 - 2.32 (m, 1H), 2.06 - 2.00 (m, 1H), 1.94 - 1.88 (m, 1H), 0.93 (s, 9H). HRMS (ESI) calcd for C₃₄H₅₁N₄O₁₀S⁺ [M +H]^÷, 707.3320; found, 707.2945.

Intermediate Example 21: synthesis of (S)-21-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16-pentaoxa-20-azatricosanoic acid (SIAIS151009)

According to the procedures for the preparation of Intermediate Example 17, 4,7,10,13,16-pentaoxanonadecanedioic acid was used to prepare SIAIS151009 (white solid, 0.82 g, 85% yield). ¹H NMR (500 MHz, DMSO) δ 8.98 (s, 1H), 8.56 (d, J = 5.7 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.40 (dd, J= 18.6, 7.9 Hz, 4H), 4.55 (d, J = 9.3 Hz, 1H), 4.47 - 4.40 (m, 2H), 4.35 (s, 1H), 4.22 (dd, J = 15.7, 5.2 Hz, 1H), 3.68 - 3.56 (m, 11H), 3.51 - 3.49 (s, 9H), 2.56 - 2.53 (m, 1H), 2.45 - 2.41 (m, 5H), 2.44 (s, 3H), 2.36 (dd, J = 13.4, 7.0 Hz, 1H), 2.08 - 2.00 (m, 1H), 1.94 - 1.86 (m, 1H), 0.93 (s, 9H). HRMS (ESI) calcd for C₃₆H₅₅N₄O₁₁S⁺ [M +H]⁺ , calcd for 751.3583; found, 751.3199.

Intermediate Example 22: synthesis of 4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (SIAIS074011)

According to scheme 6, to a solution of diacid (succinic acid, 5.0 mmol, 2.5 equiv) in anhydrous DMF (10 mL) and anhydrous DCM (150 mL) was added NMM (10.0 mmol, 5 equiv), VHL-1 (2 mmol, 1 equiv), HOAt (2.4 mmol, 1.2 equiv) and EDCI (2.4 mmol, 1.2 equiv) at 0 °C. The resulting reaction solution was stirred at 0 °C for 5 h and then at room temperature overnight. After VHL-1 was totally consumed, the reaction was quenched with water (1 mL) and then concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1%TFA) = 10% -100%, to yield the desired product SIAIS074011 as white solid (0.82 g, 65%). ¹H NMR (500 MHz, CDCl₃) δ 11.88 (s, 1H), 8.85 (s, J = 11.2 Hz, 1H), 7.69 (s, 1H), 7.37 - 7.29 (m, 4H), 6.09 (br, 1H), 4.67 - 4.54 (m, 3H), 4.49 (s, 1H), 4.29 (dd, J = 15.0, 5.0Hz, 1H), 4.05 (d, J = 11.3 Hz, 1H), 3.73 - 3.63 (m, 1H), 2.73 - 2.58 (m, 1H), 2.57 - 2.41 (m, 3H), 2.50 (s, 3H), 2.31 - 2.14 (m, 2H), 0.96 (s, 9H). HRMS (ESI) calcd for C₂₆H₃₅N₄O₆S⁺ [M + H]⁺, 531.2272; found, 531.2275.

Intermediate Example 23: synthesis of 5-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentanoic acid (SIAIS074012)

According to the procedures for the preparation of Intermediate Example 22, glutaric acid was used to prepare SIAIS074012 (white solid, 0.85 g, 67% yield). ¹H NMR (500 MHz, CDCl₃) δ 9.08 (s, 1H), 8.65 (br, 1H), 8.10 (s, 1H), 7.38 - 7.29 (m, 4H), 4.72 - 4.64 (m, 3H), 4.52 (s, 1H), 4.25 (dd, J = 15.4, 5.0 Hz, 1H), 4.09 (d, J = 10.5 Hz, 1H), 3.73 (d, J = 10.0 Hz, 1H), 2.48 (s, 3H), 2.39 - 2.13 (m, 6H), 1.92 - 1.74 (m, 2H), 0.96 (s, 9H). HRMS (ESI) calcd for C₂₇H₃₇N₄O₆S⁺ [M + H]⁺, 545.2428; found, 545.2428.

Intermediate Example 24: synthesis of 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoic acid (SIAIS074013)

According to the procedures for the preparation of Intermediate Example 22, adipic acid was used to prepare SIAIS074013 (white solid, 0.79 g, 55% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.99 (s, 1H), 7.66 (s, 1H), 7.39 - 7.33 (m, 4H), 7.30 (d, J = 7.5 Hz, 1H). 7.14 (br, 1H), 4.67 - 4.61 (m, 3H), 4.52 (s, 1H). 4.28 (dd, J = 15.4, 5.0 Hz, 1H), 4.09 (d, J = 11.4 Hz, 1H), 3.74 - 3.63 (m, 1H), 2.52 (s, 3H), 2.31 - 2.17 (m, 6H), 1.65 - 1.53 (m, 4H), 0.96 (s, 9H). HRMS (ESI) calcd for calcd for C₂₈H₄₀N₄O₆S⁺ [M + H]⁺, 559.2585; found, 559.3632.

Intermediate Example 25: synthesis of 7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid (SIAIS074014)

According to the procedures for the preparation of Intermediate Example 22, pimelic acid was used to prepare SIAIS074014 (white solid, 0.8 g, 57% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.90 (s, 1H), 7.42 - 7.38 (m, 1H), 7.41 - 7.33 (m, 4H), 7.31 (d, J = 90 Hz, 1H), 6.38 (br, 1H), 4.79 - 4.46 (m, 3H), 4.55 (s, 1H), 4.28 (dd, J = 15.2, 5.1 Hz, 1H), 4.12 (d, J = 11.3 Hz, 1H), 3.72 - 3.63 (m, 1H), 2.51 (s, 3H), 2.38 - 2.33 (m, 1H), 2.28 - 2.21 (m, 4H), 2.18 - 2.12 (m, 1H), 1.62 - 1.52 (m, 3H), 1.33 - 1.23 (m, 3H), 0.96 (s, 9H). HRMS (ESI) calcd for C₂₉H₄₁N₄O₆S⁺ [M + H]⁺, 573.2741; found, 573.3804.

Intermediate Example 26: synthesis of 8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoic acid (SIAIS074015)

According to the procedures for the preparation of Intermediate Example 22, suberic acid was used to prepare SIAIS074015 (white solid, 0.95 g, 68% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.82 (s, 1H), 7.43 (t, J = 6.0 Hz, 1H), 7.34 (s, 4H), 6.98 (d, J = 8.5 Hz, 1H), 6.10 (s, 1H), 4.69 - 4.65 (m, 1H), 4.63 - 4.51 (m, 2H), 4.55 - 4.50 (m, 1H), 4.38 - 4.27 (m, 1H), 4.11 (d, J = 16.7 Hz, 1H), 3.72 - 3.62 (m, 1H), 2.51 (s, 3H), 2.39 - 2.13 (m, 6H), 1.58 - 1.54 (m, 4H), 1.33 - 1.21 (m, 4H), 0.95 (s, 9H). HRMS (ESI) calcd for C₃₀H₄₃N₄O₆S⁺ [M + H]⁺, 587.2898; found, 587.2917.

Intermediate Example 27: synthesis of 9-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononanoic acid (SIAIS074016)

According to the procedures for the preparation of Intermediate Example 22, azelaic acid was used to prepare SIAIS074016 (white solid, 0.92 g, 64% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.82 (s, 1H), 7.35 (s, 4H), 7.02 (t, J = 14.3 Hz, 1H), 5.99 (s, 1H), 4.74 - 4.49 (m, 4H), 4.30 (dd, J = 15.2, 5.1 Hz, 1H), 4.13 (d, J = 11.3 Hz, 1H), 3.67 (dd, J = 11.5, 3.5 Hz, 1H), 2.51 (s, 3H), 2.42 - 2.36 (m, 1H), 2.28 (t, J = 7.5 Hz, 2H), 2.24 - 2.12 (m, 3H), 1.67 - 1.48 (m, 4H), 1.35 - 1.22 (m, 6H), 0.95 (s, 9H). HRMS (ESI) calcd for C₃₁H₄₅N₄O₆S⁺ [M + H]⁺, 601.3054; found, 601.3150.

Intermediate Example 28: synthesis of 10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoic acid (SIAIS074019)

According to the procedures for the preparation of Intermediate Example 22, sebacic acid was used to prepare SIAIS074019 (white solid, 0.96 g, 66% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.79 (s, 1H), 7.39 - 7.36 (m, 1H), 7.35 (s, 4H), 7.01 (d, J = 9.0 Hz, 1H), 5.80 (s, 1H), 4.68 - 4.52 (m, 4H), 4.29 (dd, J = 15.2, 5.0 Hz, 1H), 4.12 (d, J = 11.2 Hz, 1H), 3.72 - 3.62 (m, 1H), 2.51 (s, 3H), 2.41 - 2.33 (m, 1H), 2.32 - 2.23 (m, 2H), 2.23 - 2.11 (m, 3H), 1.65 - 1.48 (m, 4H), 1.32 - 1.21 (m, 8H), 0.95 (s, 9H). HRMS (ESI) calcd for C₃₂H₄₇N₄O₆S⁺ [M + H]⁺ : 615.3211; found, 615.4391.

Intermediate Example 29: synthesis of 11-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecanoic acid (SIAIS074020)

According to the procedures for the preparation of Intermediate Example 22, 1,11-undecanedioic acid was used to prepare SIAIS074020 (white solid, 1 g, 67% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.77 (s, 1H), 7.39 - 7.32 (m, 4H), 7.30 (m, 1H), 7.01 (d, J = 8.8 Hz, 1H), 5.52 (br, 1H), 4.69 - 4.59 (m, 3H), 4.53 (s, 1H), 4.29 (dd, J = 15.2, 5.0 Hz, 1H), 4.14 (d, J = 11.3 Hz, 1H), 3.68 - 3.64 (m, 1H), 2.51 (s, 3H), 2.44 - 2.40 (m, 1H), 2.29 (t, J= 7.1 Hz, 2H), 2.26 - 2.12 (m, 3H), 1.68 - 1.48 (m, 4H), 1.30 - 1.20 (m, 10H), 0.95 (s, 9H). HRMS (ESI) calcd for C₃₃H₄₉N₄O₆S⁺ [M + H]⁺, 629.3367; found, 629.4540.

Intermediate Example 30: synthesis of 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxopropanoic acid (SIAIS171004)

According to scheme 7, to a solution of diacid (malonic acid, 5.0 mmol, 2.5 equiv) in anhydrous DMF (10 mL) and anhydrous DCM (150 mL) was added NMM (10.0 mmol, 5 equiv), lenalidomide (2 mmol, 1 equiv), HOAt (2.4 mmol, 1.2 equiv) and EDCI (2.4 mmol, 1.2 equiv) at 0 °C. The resulting reaction solution was then stirred at room temperature overnight. After lenalidomide was totally consumed, the reaction was quenched with water (1 mL) and then concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1%TFA) = 10% -100%, to yield the desired product SIAIS171004 as white solid (0.32 g, 24%). ¹H NMR (500 MHz, DMSO) δ 11.02 (s, 1H), 10.03 (s, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.62 - 7.43 (m, 2H), 5.15 (dd, J = 13.4, 4.9 Hz, 1H), 4.36 (dd, J = 35.5, 17.5 Hz, 2H), 3.42 (s, 2H), 2.95 - 2.87 (m, 1H), 2.63 - 2.59 (m, 1H), 2.38 - 2.28 (m, 1H), 2.07 - 2.01 (m, 1H). HRMS (ESI) calcd for C₁₆H₁₆N₃O₆ ⁺ [M+H]⁺, 346.1034; found, 346.1015.

Intermediate Example 31: synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-4-oxobutanoic acid (SIAIS164084)

According to the procedures for the preparation of Intermediate Example 30, succinic acid was used to prepare SIAIS164084 (white solid, 0.11 g, 44% yield). ¹H NMR (500 MHz, DMSO) δ 12.16 (s, 1H), 11.02 (s, 1H), 9.86 (s, 1H), 7.81 (dd, J = 7.1, 1.7 Hz, 1H), 7.57 - 7.40 (m, 2H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 (dd, J = 35.5, 17.5 Hz, 2H), 2.96 - 2.87 (m, 1H), 2.65 - 2.58 (m, 3H), 2.55 - 2.53 (m, 2H), 2.37 - 2.29 (m, 1H), 2.06 - 2.00 (m, 1H). HRMS (ESI) calcd for C₁₇H₁₈N₃O₆ ⁺ [M+H]⁺, 360.1190; found, 360.1198.

Intermediate Example 32: synthesis of 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-5-oxopentanoic acid (SIAIS171005)

According to the procedures for the preparation of Intermediate Example 30, glutaric acid was used to prepare SIAIS171005 (white solid, 0.52 g, 35% yield). ¹H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 9.80 (s, 1H), 7.81 (d, J = 5.8 Hz, 1H), 7.54 - 7.46 (m, 2H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 (dd, J = 35.5, 17.5 Hz, 2H), 2.97 - 2.85 (m, 1H), 2.77 - 2.75 (m, 2H), 2.66 - 2.57 (m, 1H), 2.42 - 2.39 (m, 1H), 2.35 (dd, J = 13.1, 4.4 Hz, 1H), 2.30 - 2.27 (m, 1H), 2.03 - 1.97 (m, 1H), 1.85 - 1.79 (m, 2H). HRMS (ESI) calcd for C₁₈H₂₀N₃O₆ ⁺ [M+H]⁺, 374.1347; found, 374.1526.

Intermediate Example 33: synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-6-oxohexanoic acid (SIAIS164101)

According to the procedures for the preparation of Intermediate Example 30, adipic acid was used to prepare SIAIS164101 (white solid, 0.4 g, 27% yield). ¹H NMR (500 MHz, MeOD) δ 7.70 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 5.16 (dd, J = 13.4, 5.2 Hz, 1H), 4.53 - 4.43 (m, 2H), 2.95 - 2.87 (m, 1H), 2.81 - 2.76 (m, 1H), 2.55 - 2.48 (m, 1H), 2.46 (t, J = 7.2 Hz, 2H), 2.36 (t, J = 7.0 Hz, 2H), 2.22 - 2.16 (m, 1H), 1.79 - 1.66 (m, 4H). HRMS (ESI) calcd for C₁₉H₂₂N₃O₆ ⁺ [M+H]⁺, 388.1503; found, 388.1714.

Intermediate Example 34: synthesis of 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-7-oxoheptanoic acid (SIAIS164102)

According to the procedures for the preparation of Intermediate Example 30, pimelic acid was used to prepare SIAIS164102 (white solid, 0.45 g, 28% yield). ¹H NMR (500 MHz, MeOD) δ 7.70 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 5.16 (dd, J = 13.4, 5.2 Hz, 1H), 4.49 (t, J = 10.1 Hz, 2H), 2.94 - 2.87 (m, 1H), 2.81 - 2.76 (m, 1H), 2.54 - 2.48 (m, 1H), 2.45 (t, J = 7.5 Hz, 2H), 2.32 (t, J = 7.0 Hz, 2H), 2.22 - 2.16 (m, 1H), 1.77 - 1.72 (m, 2H), 1.70 - 1.63 (m, 2H), 1.48 - 1.42 (m, 2H). HRMS (ESI) calcd for C₂₀H₂₄N₃O₆ ⁺ [M+H]⁺, 402.1660; found, 402.1890.

Intermediate Example 35: synthesis of (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)aminoacetic acid (SIAIS1204057)

According to scheme 8, to a solution of lenalidomide (2 mmol, 1 equiv) in NMP (8 mL) was added tert-butyl 2-bromoacetate (2.4 mmol, 1.2 equiv) and DIPEA (6 mmol, 3 equiv), then stirred at 110 °C overnight. After cooling to room temperature, the resulting solution was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1%TFA) = 10% -100%, to yield the desired tert-butyl ester intermediate. This intermediate was treated with TFA (2 mL) in DCM (6 mL) for 1 h at room temperature. After concentration under reduced pressure and freeze-drying, the desired product SIAIS1204057 was obtained as yellow solid, 1.0 g, 48%. ¹H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.94 (s, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.26 (d, J = 17.0 Hz, 1H), 4.16 (d, J = 17.0 Hz, 1H), 3.92 (s, 2H), 2.98 - 2.85 (m, 1H), 2.62 (d, J = 17.3 Hz, 1H), 2.39-2.26 (m, 1H), 2.08-1.99 (m, 1H). HRMS (ESI) calcd for C₁₅H₁₆N₃O₅ ⁺ [M+H]⁺, 318.1084; found, 318.1098.

Intermediate Example 36: synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanoic acid (SIAIS1204085)

According to the procedures for the preparation of Intermediate Example 35, tert-butyl 4-bromobutanoate was used to prepare SIAIS1204085 (yellow solid, 215 mg, 62% yield). ¹H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.23 (d, J = 17.0 Hz, 1H), 4.13 (d, J = 17.0 Hz, 1H), 4.01 (s, 1H), 3.14 (t, J = 7.0 Hz, 2H), 2.98 - 2.86 (m, 1H), 2.66 - 2.58 (d, J = 17.6 Hz, 1H), 2.34 (t, J = 7.3 Hz, 2H), 2.32 - 2.24 (m, 1H), 2.08 - 1.98 (m, 1H), 1.85 - 1.75 (m, 2H). HRMS (ESI) calcd for C₁₇H₂₀N₃O₅ ⁺ [M+H]⁺, 346.1379; found, 346.1414.

Intermediate Example 37: synthesis of 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoic acid (SIAIS1210133)

According to the procedures for the preparation of Intermediate Example 35, tert-butyl 5-bromopentanoate was used to prepare SIAIS1210133 (yellow solid, 215 mg, 60% yield). ¹H NMR (500 MHz, DMSO) δ 11.00 (s, 1H), 7.28 (t, J= 7.7 Hz, 1H), 6.92 (t, J= 10.9 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 5.07 (s, 1H), 4.23 (d, J = 17.2 Hz, 1H), 4.13 (d, J = 17.1 Hz, 1H), 3.13 (d, J = 6.4 Hz, 2H), 2.97 - 2.87 (m, 1H), 2.61 (d, J = 16.7 Hz, 1H), 2.38 - 2.21 (m, 3H), 2.06 - 1.98 (m, 1H), 1.67 - 1.55 (m, 4H). HRMS (ESI) calcd for C₁₈H₂₂N₃O₅ ⁺ [M+H]⁺, 360.1554; found, 360.1551.

Intermediate Example 38: synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoic acid (SIAIS1204061)

According to the procedures for the preparation of Intermediate Example 35, tert-butyl 6-bromohexanoate was used to prepare SIAIS1204061 (yellow solid, 268 mg, 72% yield). ¹H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.24 (d, J = 17.0 Hz, 1H), 4.14 (d, J = 17.0 Hz, 1H), 4.05 (s, 1H), 3.12 (t, J = 7.0 Hz, 2H), 2.98 - 2.87 (m, 1H), 2.66 - 2.58 (m, 1H), 2.35 - 2.25 (m, 1H), 2.22 (t, J = 7.0 Hz, 2H), 2.07 - 2.00 (m, 1H), 1.63 - 1.50 (m, 4H), 1.43 - 1.37 (m, 2H). HRMS (ESI) calcd for C₁₉H₂₄N₃O₅ ⁺ [M+H]⁺, 374.1710; found, 374.1720.

Intermediate Example 39: synthesis of 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptanoic acid (SIAIS1204063)

According to the procedures for the preparation of Intermediate Example 35, tert-butyl 7-bromoheptanoate was used to prepare SIAIS1204063 (yellow solid, 252 mg, 65% yield). ¹H NMR (500 MHz, DMSO) δ 11.00 (s, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.23 (d, J = 17.0 Hz, 1H), 4.13 (d, J = 17.0 Hz, 1H), 3.11 (t, J = 7.0 Hz, 2H), 2.98 - 2.84 (m, 1H), 2.67 - 2.57 (m, 1H), 2.35 - 2.25 (m, 1H), 2.20 (t, J = 7.3 Hz, 2H), 2.07 - 1.99 (m, 1H), 1.63 - 1.46 (m, 4H), 1.42 - 1.27 (m, 4H). HRMS (ESI) calcd for C₂₀H₂₆N₃O₅ ⁺ [M+H]⁺, 388.1867; found, 388.1878.

Intermediate Example 40: synthesis of 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl) isoindolin-1,3-dione (SIAIS151103)

According to Scheme 9, a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (7.2 mmol, 1 equiv), tert-butyl(2-aminoethyl)carbamate (8.1 mmol, 1.2 equiv) and DIPEA (36.4 mmol, 5 equiv) in NMP (10 mL) was stirred in a microwave tube for 10 min at room temperature, then charged with argon and heated to 110 °C in a microwave reactor for 2 h. After cooling to RT, the reaction mixture was poured into 90% saline, extracted with EA(4 x 50 mL), the combined organic phase was washed with water (2 x 30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent(v/v): hexanes/EA = 1:1) to give the desired tert-butyl ester intermediate. This intermediate was treated with 88% formic acid (20 mL) overnight at room temperature. After concentration under reduced pressure and freeze-drying, the desired product SIAIS151103 was obtained as yellow solid (1.1 g, 48% yield). ¹H NMR (500 MHz, DMSO) δ 8.36 (s, 2H), 7.64 - 7.58 (m, 1H), 7.18 (t, J = 6.2 Hz, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.84 (t, J = 6.2 Hz, 1H), 5.06 (dd, J = 12.7, 5.4 Hz, 1H), 3.56 (dd, J = 12.2, 6.0 Hz, 2H), 2.96 (t, J = 6.1 Hz, 2H), 2.93 - 2.85 (m, 1H), 2.61 - 2.51 (m, 2H), 2.06 - 2.00 (m, 1H). HRMS (ESI) calcd for C₁₅H₁₇N₄O₄ ⁺ [M+H]⁺, 317.1244; found, 317.1236.

Intermediate Example 41: synthesis of 4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-4-oxobutanoic acid (SIAIS164119)

According to scheme 10, to a solution of succinic acid (295.2 mg, 2.5 mmol, 2.5 equiv) in anhydrous DMF (5 mL) and anhydrous DCM (50 mL) was added NMM (1.01 g, 10.0 mmol, 10 equiv), SIAIS151103 (316.3 mg, 1 mmol, 1 equiv), HOAt (163.3 mg, 1.2 mmol, 1.2 equiv) and EDCI (230 mg, 1.2 mmol, 1.2 equiv) at 0 °C. The resulting reaction solution was stirred at 0 °C for 5 h and then at room temperature overnight. After the reaction was complete, the resulting solution was quenched with water (1 mL) and then concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v) : acetonitrile/(water+0.1%TFA) = 10% -100%, to yield the desired product SIAIS164119 as yellow solid (170 mg, 41%). ¹H NMR (500 MHz, MeOD) δ 7.55 - 7.50 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.04 (t, J = 6.3 Hz, 1H), 5.05 (dd, J = 12.4, 5.5 Hz, 1H), 3.47-3.39 (m, 4H), 2.89-2.82 (m, 1H), 2.79 - 2.65 (m, 2H), 2.58 (t, J = 7.0 Hz, 2H), 2.45 (t, J = 7.0 Hz, 2H), 2.16 - 2.05 (m, 1H). HRMS (ESI) calcd for C₁₉H₂₁N₄O₇ ⁺ [M+H]⁺, 417.1405; found, 417.0916.

Intermediate Example 42: synthesis of (2S,4R)-1-((S)-2-(4-azidobutyrylamino-3,3-dimethylbutyryl) -4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide (SIAIS164050)

According to scheme 11, to a solution of VHL-1 (934 mg, 2 mmol, 1 equiv) and 4-azidobutanoic acid (258.2 mg, 2 mmol, 1 equiv) in DMF (5 mL) and DCM (20 mL) was added HOAt (54.4 mg, 0.4 mmol, 0.2 equiv), EDCI (766.8 mg, 4 mmol, 2 equiv) and NMM (2.02 g, 20 mmol, 10 equiv) at room temperature. The resulting reaction solution was stirred at room temperature overnight. After the reaction was complete detected by LC-MS, the resulting solution was concentrated under reduced pressure, the residue was poured into 90% saline, extracted with EA(4 x 50 mL), the combined organic phase was washed with water (2 x 30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent(v/v): DCM/MeOH = 40:1) to give the desired product SIAIS164050 as pale yellow liquid (734 mg, 68%). ¹H NMR (500 MHz, MeOD) δ 8.87 (s, 1H), 7.48 - 7.41 (m, 4H), 4.62 (s, 1H), 4.58-4.50 (m, 3H), 4.38 - 4.33 (m, 1H), 3.91 (d, J = 11.0 Hz, 1H), 3.80 (dd, J = 10.9, 3.9 Hz, 1H), 3.33 (t, J = 5.0 Hz, 2H), 2.48 (d, J = 5.3 Hz, 3H), 2.41 - 2.32 (m, 2H), 2.22 (dd, J = 13.1, 7.6 Hz, 1H), 2.11-2.06 (m, 1H), 1.90- 1.82 (m, 2H), 1.04 (s, 9H). HRMS (ESI) calcd for C₂₆H₃₆N₇O₄S⁺ [M+H]⁺, 542.2544; found, 542.2256.

Intermediate Example 43: synthesis of 4-(1-(4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobut-2-yl)amino)-4-oxobutyl)-1H-1,2,3-triazol-4-yl)butanoic acid (SIAIS164128):

According to scheme 12, to a solution of 5-hexynoic acid (22.4 mg, 0.2 mmol, 1 equiv) and SIAIS164050 (108.3 mg, 0.2 mmol, 1 equiv) in DMF (1 mL), tBuOH (1 mL) and water (1 mL) was added CuSO₄ (31.9 mg, 0.2 mmol, 1 equiv) and sodium ascorbate (39.6 mg, 0.2 mmol, 1 equiv) at room temperature. The resulting reaction solution was stirred at room temperature for 2 h. After the reaction was complete detected by LC-MS, the resulting solution was purified by reverse-phase chromatography (eluent (v/v): acetonitrile/(water+0.1%TFA) = 10% -100%), to yield the desired product SIAIS164128 as white solid (100 mg, 76%). ¹H NMR (500 MHz, MeOD) δ 9.19 (d, J = 3.4 Hz, 1H), 7.87 (s, 1H), 7.51 - 7.42 (m, 4H), 4.60 (s, 1H), 4.59-4.54 (m, 2H), 4.51 (s, 1H), 4.43 (t, J = 6.8 Hz, 2H), 4.36 (d, J = 15.3 Hz, 1H), 3.93 (d, J = 11.1 Hz, 1H), 3.80 (dd, J = 11.0, 3.8 Hz, 1H), 2.77 (t, J = 7.6 Hz, 2H), 2.51 (d, J = 3.8 Hz, 3H), 2.36 (t, J = 7.3 Hz, 2H), 2.32-2.28 (m, 2H), 2.25 - 2.15 (m, 3H), 2.11-2.06 (m, 1H), 2.00-1.94 (m, 2H), 1.04 (s, 9H). HRMS (ESI) calcd for C₃₂H₄₄N₇O₆S⁺ [M+H]⁺, 654.3068; found, 654.2990.

Intermediate Example 44: synthesis of 11-(((S)-1-((2S,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecanoic acid (SIAIS219048):

According to scheme 13, to a solution of diacid (1,11-undecanedioic acid, 0.25 mmol, 2.5 equiv) in anhydrous DMF (4 mL) and anhydrous DCM (10 mL) was added NMM (0.5 mmol, 5 equiv), trans-VHL-1 (0.1 mmol, 1 equiv), HOAt (0.15 mmol, 1.5 equiv) and EDCI (0.15 mmol, 1.5 equiv) at 0 °C. The resulting reaction solution was stirred at 0 °C for 2 h and then at room temperature overnight. After trans-VHL-1 was totally consumed, the reaction was quenched with water (1 mL) and then concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1%TFA) = 10% -100%, to yield the desired product SIAIS219048 as white solid (48 mg, 76%). ¹H NMR (500 MHz, CDCl₃) δ 8.78 (s, 1H), 7.38 - 7.31 (m, 4H), 7.31-7.28 (m, 1H), 7.00 (d, J = 8.8 Hz, 1H), 5.50 (br, 1H), 4.67 - 4.56 (m, 3H), 4.51 (s, 1H), 4.26 (dd, J = 15.2, 5.0 Hz, 1H), 4.13 (d, J = 11.3 Hz, 1H), 3.64 - 3.62 (m, 1H), 2.50 (s, 3H), 2.43 - 2.40 (m, 1H), 2.27 (t, J = 7.1 Hz, 2H), 2.25 - 2.11 (m, 3H), 1.67 - 1.46 (m, 4H), 1.30 - 1.21 (m, 10H), 0.93 (s, 9H). HRMS (ESI) calcd for C₃₃H₄₉N₄O₆S⁺ [M + H]⁺, 629.3367; found, 629.3377.

Intermediate Example 45: synthesis of 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl) propionic acid (SIAIS172147):

Synthesis of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (SIAIS172136):

According to scheme 14, 4-bromoisobenzofuran-1,3-dione (500 mg, 2.20 mmol), 3-aminopiperidine-2,6-dione (400 mg, 2.42 mmol) and anhydrous sodium acetate was added in a 100 mL egg-shaped flask, followed by glacial acetic acid (10 mL). The resulting reaction solution was slowly heated to 140 °C and stirred for 12 h. After the reaction was complete, the reaction solution was cooled to room temperature, a large amount of white solid was precipitated. After filtration, the filter cake, water (10 mL) and methanol (2 mL) were added to a flask and stirred for 0.5 h. After filtration, the filter cake was washed with water, concentrated under reduced pressure to yield the desired product SIAIS172136 as white solid (700 mg, 94%). ¹H NMR (500 MHz, DMSO) δ 11.14 (s, 1H), 8.14 (d, J = 1.4 Hz, 1H), 8.09 (dd, J = 7.9, 1.7 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 5.16 (dd, J = 12.9, 5.4 Hz, 1H), 2.93 - 2.85 (m, 1H), 2.65 - 2.50 (m, 2H), 2.08 - 2.04 (m, 1H). HRMS (ESI) calcd for C₁₃H₁₀BrN₂O₄ ⁺ [M+H]⁺, 336.9818; found, 336.9810.

Synthesis of tert-butyl (E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acrylate (SIAIS172145):

According to scheme 14, tri-tert-butylphosphine tetrafluoroborate (110 mg, 0.38 mmol), N-methyldicyclohexylamine (250 mg, 1.28 mmol), Pd₂(dba)₃(163 mg, 0.64 mmol) and anhydrous dioxane was added in a 50 mL egg-shaped flask and stirred at room temperature for 30 min, then SIAIS172136 (300 mg, 0.89 mmol) and tert-butyl acrylate were added. The resulting reaction solution was slowly heated to 55 °C under an atmosphere of nitrogen and stirred for 12 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure,the residue was purified by silica gel chromatography (eluent(v/v): EA/PE = 2:3) to yield the desired product SIAIS172145 as light yellow solid (270 mg, 79%). ¹H NMR (500 MHz, CDCl₃) δ 8.11 (s, 1H), 8.02 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.84 (dd, J = 7.8, 1.2 Hz, 1H), 7.65 (d, J = 16.0 Hz, 1H), 6.54 (d, J = 16.0 Hz, 1H), 5.00 (dd, J = 12.5, 5.3 Hz, 1H), 2.94 - 2.72 (m, 3H), 2.20 - 2.13 (m, 1H), 1.54 (s, 9H). HRMS (ESI) calcd for C₂₀H₂₁N₂O₆ ⁺ [M+H]⁺, 385.1394; found, 385.1389.

Synthesis of 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl) propionic acid (SIAIS172147):

According to scheme 14, SIAIS172145 (250 mg, 0.65 mmol) was added in a 100 mL egg-shaped flask, followed by dioxane (20 mL) anad 10% wet Pd/C. After extracting and recharging with H₂ (25 psi) 3 times, the reaction solution was allowed to stir at RT overnight. After the reaction was complete, the reaction solution was filtrated, washed with dioxane, the filtrate was concentrated under reduced pressure to give a light yellow oil, the crude was used for the following reaction without further purification. The crude, TFA (1 mL) and anhydrous DCM were added in a 50 mL egg-shaped flask, and stirred at RT for 2 h, when the reaction was complete, the resulting solution was concentrated under reduced pressure, the residue was purified by reverse-phase chromatography, eluent (v/v): acetonitrile/(water+0.1%TFA) = 10% - 100%, to yield the desired product SIAIS172147 after concentration and freeze-drying, (white solid, 180 mg, 84% over 2 steps). ¹H NMR (500 MHz, DMSO) δ 12.22 (s, 1H), 11.12 (s, 1H), 7.86 - 7.79 (m, 2H), 7.77 - 7.70 (m, 1H), 5.13 (dd, J = 12.8, 5.4 Hz, 1H), 3.01 (t, J = 7.4 Hz, 2H), 2.93 - 2.85 (m, 1H), 2.64 (t, J = 7.4 Hz, 2H), 2.62 - 2.50 (m, 2H), 2.08 - 2.02(m, 1H). HRMS (ESI) calcd for C₁₆H₁₅N₂O₆ ⁺ [M+H]⁺, 331.0925; found, 331.0919.

Compound Examples

Compound Example 1: synthesis of 4-((2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197065)

According to scheme 15, to a stirred solution of corresponding ALK inhibitor (Brigatinib Analogue A, 0.02 mmol, 1 equiv) and intermediate LM (SIAIS151001, 0.02 mmol, 1 equiv), in DMF (1 mL) and DCM (5 mL) was added HOAt (0.04 mmol, 2 equiv), EDCI (0.04 mmol, 2 equiv) and NMM (0.2 mmol, 10 equiv) sequentially at RT. The resulting reaction mixture was stirred at room temperature overnight. After the reaction was complete detected by LC-MS, the resulting solution was was purified by preparative HPLC, eluent (v/v): acetonitrile/(water+0.05%HCl) = 10% -100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS1197065 was obtained as yellow solid (16.2 mg, 60%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.05 (s, 1H), 7.65 (dd, J = 13.8, 7.7 Hz, 1H), 7.54 (s, 1H), 7.50 (dd, J = 8.4, 7.2 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.26 (s, 1H), 7.04 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 7.1 Hz, 1H), 6.65 (s, 1H), 6.46 (d, J = 7.9 Hz, 1H), 4.97 (dd, J = 12.4, 5.4 Hz, 1H), 3.84 (t, J = 5.8 Hz, 4H), 3.80 (s, 3H), 3.72 (t, J = 5.0 Hz, 4H), 3.48 (t, J = 5.0 Hz, 2H), 3.20 (s, 4H), 2.80 - 2.68 (m, 3H), 2.66 - 2.58 (m, 2H), 2.04 - 1.96 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₁H₄₆ClN₉O₈P⁺ [M+H]⁺, 858.2890; found, 858.3506.

Compound Example 2: synthesis of 4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197067)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151004) was used to prepare SIAIS1197067 (yellow solid, 16.7 mg, 62% yield). ¹H NMR (500 MHz, MeOD) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J = 13.9, 7.7 Hz, 1H), 7.55 (s, 1H), 7.50 (dd, J = 8.5, 7.2 Hz, 1H), 7.37 (t, J = 7.0 Hz, 1H), 7.28 (d, J = 6.7 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H), 6.51 (d, J = 6.4 Hz, 1H), 5.02 (dd, J = 12.5, 5.5 Hz, 1H), 3.82 (s, 3H), 3.79 (t, J = 6.1 Hz, 2H), 3.74 (d, J = 4.2 Hz, 4H), 3.68 (t, J = 5.3 Hz, 2H), 3.66 - 3.59 (m, 4H), 3.43 (t, J = 5.2 Hz, 2H), 3.28 - 3.18 (m, 4H), 2.86 - 2.76 (m, 1H), 2.75 - 2.61 (m, 4H), 2.11 - 2.03 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₃H₅₀ClN₉O₉P⁺ [M+H]⁺, 902.3152; found, 902.3791.

Compound Example 3: synthesis of 4-((2-(2-(2-(3-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197069)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151005) was used to prepare SIAIS1197069 (yellow solid, 13.7 mg, 51% yield). ¹H NMR (500 MHz, MeOD) δ 8.36 (s, 1H), 8.03 (s, 1H), 7.66 (dd, J = 14.0, 7.7 Hz, 1H), 7.55 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.30 (s, 1H), 7.03 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.70 (s, 1H), 6.56 (s, 1H), 5.02 (dd, J = 12.6, 5.5 Hz, 1H), 3.83 (s, 3H), 3.80 - 3.71 (m, 6H), 3.68 - 3.57 (m, 10H), 3.44 (t, J = 5.0 Hz, 2H), 3.28 (s, 2H), 3.23 (s, 2H), 2.87 - 2.78 (m, 1H), 2.75 - 2.62 (m, 4H), 2.12 - 2.04 (m, 1H), 1.88 (d, J= 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₅H₅₄ClN₉O₁₀P⁺ [M+H]⁺, 946.3961; found, 946.1771.

Compound Example 4: synthesis of 4-((15-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197071)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151006) was used to prepare SIAIS1197071 (yellow solid, 4.8 mg, 18% yield). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.03 (s, 1H), 7.66 (dd, J = 15.0, 7.4 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.37 (t, J = 8.4 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.07 - 7.00 (m, 2H), 6.72 (s, 1H), 6.56 (s, 1H), 5.02 (dd, J = 12.6, 5.5 Hz, 1H), 3.84 (s, 3H), 3.80 - 3.73 (m, 6H), 3.64 - 3.55 (m, 14H), 3.46 (t, J = 5.5 Hz, 2H), 3.24 (s, 4H), 2.87 - 2.78 (m, 1H), 2.74 - 2.67 (m, 4H), 2.10 - 2.04 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₇H₅₈ClN₉O₁₁P⁺ [M+H]⁺, 990.3676; found, 990.4374.

Compound Example 5: synthesis of 4-((18-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197073)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151007) was used to prepare SIAIS1197073 (yellow solid, 4.5 mg, 17% yield). ¹H NMR (500 MHz, MeOD) δ 8.39 (s, 1H), 8.03 (s, 1H), 7.66 (dd, J = 14.0, 7.5 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.38 (t, J = 7.1 Hz, 1H), 7.29 (s, 1H), 7.06 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.73 (s, 1H), 6.57 (s, 1H), 5.02 (dd, J = 12.6, 5.5 Hz, 1H), 3.84 (s, 3H), 3.80 - 3.72 (m, 6H), 3.71 - 3.54 (m, 18H), 3.46 (t, J = 5.5 Hz, 2H), 3.24 (s, 4H), 2.86 - 2.77 (m, 1H), 2.76 - 2.62 (m, 4H), 2.11 - 2.04 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₉H₆₂ClN₉O₁₂P⁺ [M+H]⁺, 1034.3939; found, 1034.3055.

Compound Example 6: synthesis of 4-((2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197055)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS 151025) was used to prepare SIAIS1197055 (yellow solid, 18.8 mg, 69% yield). ¹H NMR (500 MHz, DMSO) δ 11.12 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.64 (dd , J = 8.4, 7.2 Hz, 1H), 7.59 - 7.54 (m, 1H), 7.43 (d, J = 9.4 Hz, 1H), 7.39 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 7.1 Hz, 1H), 6.73 (d, J = 2.1 Hz, 1H), 6.55 (dd, J = 8.5, 2.2 Hz, 1H), 5.08 (dd, J = 12.9, 5.1 Hz, 1H), 3.80 (s, 3H), 3.71 (s, 4H), 3.28 (s, 2H), 3.20 (s, 4H), 1.78 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₃₈H₄₀ClN₉O₇P⁺ [M+H]⁺, 800.2471; found, 800.2478.

Compound Example 7: synthesis of 4-((3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197057)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS 151026) was used to prepare SIAIS1197057 (yellow solid, 13.5 mg, 50% yield). ¹H NMR (500 MHz, MeOD) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J = 14.0, 7.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 7.1 Hz, 1H), 6.68 (s, 1H), 6.54 (d, J = 7.5 Hz, 1H), 4.99 (dd, J = 12.8, 5.5 Hz, 1H), 3.83 (s, 3H), 3.78 - 3.68 (m, 6H), 3.18 (s, 4H), 2.84 - 2.74 (m, 3H), 2.71 - 2.59 (m, 2H), 2.02 - 1.94 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₃₉H₄₂ClN₉O₇P⁺ [M+H]⁺, 814.2628; found, 814.3219.

Compound Example 8: synthesis of 4-((4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197059)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151019) was used to prepare SIAIS1197059 (yellow solid, 14.4 mg, 53% yield). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J = 13.8, 7.3 Hz, 1H), 7.54 (dd, J = 8.5, 7.1 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.69 (s, 1H), 6.54 (d, J = 7.5 Hz, 1H), 5.03 (dd, J = 12.6, 5.5 Hz, 1H), 3.84 (s, 3H), 3.78 - 3.65 (m, 4H), 3.44 (t, J = 6.6 Hz, 2H), 3.18 (s, 4H), 2.89 - 2.77 (m, 1H), 2.75 - 2.63 (m, 2H), 2.58 (t, J = 7.0 Hz, 2H), 2.11 - 2.04 (m, 1H), 2.04 - 1.97 (m, 2H), 1.88(d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₀H₄₄ClN₉O₇P⁺ [M+H]⁺, 828.2784; found, 828.2783.

Compound Example 9: synthesis of 4-((5-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197061)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS 151020) was used to prepare SIAIS1197061 (yellow solid, 12.6 mg, 45% yield). ¹H NMR (500 MHz, MeOD) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.64 (dd, J = 14.1, 7.8 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.41 - 7.30 (m, 2H), 7.07 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.69 (s, 1H), 6.53 (s, 1H), 5.00 (dd, J = 12.6, 5.5 Hz, 1H), 3.85 (s, 3H), 3.78 - 3.66 (m, 4H), 3.39 (t, J = 5.6 Hz, 2H), 3.19 (s, 4H), 2.85 - 2.74 (m, 1H), 2.73 - 2.60 (m, 2H), 2.53 (t, J = 6.6 Hz, 2H), 2.07 -2.00 (m, 1H), 1.87 (d, J = 13.5 Hz, 6H), 1.81 - 1.71 (m, 4H). HRMS (ESI) calcd for C₄₁H₄₆ClN₉O₇P⁺ [M+H]⁺, 842.2941; found, 842.2951.

Compound Example 10: synthesis of 4-((6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197063)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151027) was used to prepare SIAIS1197063 (yellow solid, 15.6 mg, 58% yield). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J = 13.5, 70 Hz, 1H), 7.53 (dd, J = 8.6, 7.1 Hz, 2H), 7.36 (t, J = 6.8 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 6.9 Hz, 1H), 6.71 (s, 1H), 6.55 (d, J = 7.7 Hz, 1H), 5.01 (dd, J = 12.5, 5.4 Hz, 1H), 3.85 (s, 3H), 3.78 - 3.68 (m, 4H), 3.36 (t, J = 6.8 Hz, 2H), 3.22 (s, 4H), 2.86 - 2.74 (m, 1H), 2.74 - 2.62 (m, 2H), 2.49 (t, J = 7.4 Hz, 2H), 2.10 - 2.03 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.76 - 1.66 (m, 4H), 1.54 - 1.46 (m, 2H). HRMS (ESI) calcd for C₄₂H₄₈ClN₉O₇P⁺ [M+H]⁺, 856.3097; found, 856.3109.

Compound Example 11: synthesis of 4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS1197077)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS 151086) was used to prepare SIAIS1197077 (yellow solid, 17.6 mg, 65% yield). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J = 13.8, 7.7 Hz, 1H), 7.53 (dd, J = 8.6, 7.1 Hz, 2H), 7.37 (t, J = 7.1 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.72 (s, 1H), 6.56 (d, J = 8.5 Hz, 1H), 5.03 (dd, J = 12.5, 5.5 Hz, 1H), 3.85 (s, 3H), 3.79 - 3.67 (m, 4H), 3.34 (t, J = 6.9 Hz, 2H), 3.24 (d, J = 14.7 Hz, 4H), 2.87 - 2.77 (m, 1H), 2.75 - 2.64 (m, 2H), 2.46 (t, J = 7.5 Hz, 2H), 2.12 - 2.04 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.74 - 1.62 (m, 4H), 1.54 - 1.40 (m, 4H). HRMS (ESI) calcd for C₄₃H₅₀ClN₉O₇P⁺ [M+H]⁺, 870.3254; found, 870.3009.

Compound Example 12: synthesis of (2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197087)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151010) was used to prepare SIAIS1197087 (white solid, 15.7 mg, 58%). ¹H NMR (500 MHz, MeOD) δ 8.85 (s, 1H), 8.37 (s, 1H), 8.04 (s, 1H), 7.65 (dd, J = 14.1, 7.4 Hz, 1H), 7.54 (s, 1H), 7.44 - 7.32 (m, 5H), 6.69 (s, 1H), 6.55 (s, 1H), 4.71 (d, J = 9.4 Hz, 1H), 4.60 - 4.44 (m, 2H), 4.50 (s, 1H), 4.41 - 4.31 (m, 3H), 4.07 (d, J = 10.4 Hz, 2H), 3.87 (d, J = 9.8 Hz, 1H), 3.83 (s, 3H), 3.80 - 3.64 (m, 9H), 3.25 (s, 4H), 2.44 (s, 3H), 2.27 - 2.17 (m, 1H), 2.13 - 2.04 (m, 1H), 1.87 (d, J = 13.5 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₁H₆₅ClN₁₀O₉PS⁺ [M+H]⁺, 1059.4077; found, 1059.4091.

Compound Example 13: synthesis of (2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197079)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151002) was used to prepare SIAIS1197079 (white solid, 14.9 mg, 55%). ¹H NMR (500 MHz, MeOD) δ 8.89 (s, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.66 (dd, J = 14.0, 7.7 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.42 - 7.33 (m, 3H), 7.29 (d, J = 7.8 Hz, 1H), 6.72 (s, 1H), 6.58 (d, J = 8.5 Hz, 1H), 4.64 (s, 1H), 4.60 - 4.52 (m, 2H), 4.49 (s, 1H), 4.34 (d, J = 15.5 Hz, 1H), 3.88 (d, J = 10.9 Hz, 1H), 3.84 (s, 3H), 3.81 - 3.66 (m, 9H), 3.62 - 3.58 (m, 4H), 3.31 (s, 2H), 3.21 (s, 2H), 2.77 - 2.66 (m, 2H), 2.46 (s, 3H), 2.51 - 2.43 (m, 1H), 2.43 - 2.36 (m, 1H), 2.25 - 2.18 (m, 1H), 2.12 - 2.04 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₃H₆₉ClN₁₀O₉PS⁺ [M+H]⁺, 1087.4390; found, 1087.3478.

Compound Example 14: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197081)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151003) was used to prepare SIAIS1197081 (white solid, 17.1 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 8.91 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J = 14.1, 7.8 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.44 - 7.35 (m, 3H), 7.29 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 2.1 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 4.64 (s, 1H), 4.59 - 4.51 (m, 2H), 4.49 (s, 1H), 4.35 (d, J = 15.5 Hz, 1H), 3.88 (d, J = 11.1 Hz, 1H), 3.85 (s, 3H), 3.82 - 3.73 (m, 7H), 3.72 - 3.65 (m, 2H), 3.63 - 3.54 (m, 8H), 3.44 (t, J = 7.0 Hz, 1H), 3.31 (s, 2H),3.24 (s, 2H), 2.71 (t, J = 6.2 Hz, 2H), 2.60 - 2.50 (m, 1H), 2.47 (s, 3H), 2.49 - 2.40 (m, 1H), 2.25 - 2.18 (m, 1H), 2.11 - 2.05 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₅H₇₃ClN₁₀O₁₀PS⁺ [M+H]⁺, 1131.4652; found, 1131.4651.

Compound Example 15: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197083)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151008) was used to prepare SIAIS1197083 (white solid, 16.7 mg, 62%). ¹H NMR (500 MHz, MeOD) δ 8.89 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.66 (dd, J = 13.5, 8.1 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.42 - 7.35 (m, 3H), 7.31 (d, J = 8.6 Hz, 1H), 6.73 (s, 1H), 6.58 (d, J = 7.5 Hz, 1H), 4.64 (s, 1H), 4.59 - 4.50 (m, 2H), 4.49 (s, 1H), 4.35 (d, J = 15.5 Hz, 1H), 3.87 (d, J = 12.2 Hz, 1H), 3.85 (s, 3H), 3.82 - 3.72 (m, 7H), 3.73 - 3.65 (m, 2H), 3.64 - 3.53 (m, 12H), 3.31 (s, 2H),3.24 (s, 2H), 2.72 (t, J = 6.2 Hz, 2H), 2.59 - 2.51 (m, 1H), 2.46 (s, 3H), 2.49 - 2.40 (m, 1H), 2.25 - 2.16 (m, 1H), 2.11 -2.04 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₇ClN₁₀O₁₁PS⁺ [M+H]⁺, 1175.4915; found, 1175.4981.

Compound Example 16: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197085)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS151009) was used to prepare SIAIS1197085 (white solid, 16.5 mg, 61%). ¹H NMR (500 MHz, MeOD) δ 8.90 (s, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 7.67 (dd, J = 14.0, 6.9 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.44 - 7.34 (m, 3H), 7.30 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 4.64 (s, 1H), 4.59 - 4.51 (m, 2H), 4.49 (s, 1H), 4.35 (d, J = 15.6 Hz, 1H), 3.88 (d, J = 11.1 Hz, 1H), 3.85 (s, 3H), 3.82 - 3.4 (m, 7H), 3.74 - 3.67 (m, 2H), 3.65 - 3.54 (m, 16H), 3.31 (s, 2H), 3.25 (s, 2H), 2.72 (t, J = 6.1 Hz, 2H), 2.60 - 2.51 (m, 1H), 2.47 (s, 3H), 2.50 - 2.40 (m, 1H), 2.25 - 2.17 (m, 1H), 2.11 - 2.04 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₉H₈₁ClN₁₀O₁₂PS⁺ [M+H]⁺, 1219.5177; found, 1219.5229.

Compound Example 17: synthesis of (2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197145)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074011) was used to prepare SIAIS1197145 (white solid, 10.1 mg, 37%). ¹H NMR (500 MHz, MeOD) δ 9.98 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.80 - 7.45 (m, 8H), 7.39 (s, 1H), 7.13 (d, J = 8.5 Hz, 1H), 4.66 - 4.35 (m, 5H), 4.05 (s, 4H), 3.96 (s, 3H), 3.89 (d, J = 10.7 Hz, 1H), 3.80 (d, J = 8.1 Hz, 1H), 3.70 (s, 2H), 3.61 (s, 2H), 2.91 - 2.63 (m, 4H), 2.61 (s, 3H), 2.23 (s, 1H), 2.07 (s, 1H), 1.87 (d, J = 13.4 Hz, 6H), 1.05 (s, 9H). HRMS (ESI) calcd for C₄₉H₆₁ClN₁₀O₇PS⁺ [M+H]⁺, 999.3866; found, 999.1918.

Compound Example 18: synthesis of (2S,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197147)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074012) was used to prepare SIAIS1197147 (white solid, 9.4 mg, 35%). ¹H NMR (500 MHz, MeOD) δ 10.00 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.79 - 7.63 (m, 3H), 7.61 - 7.46 (m, 6H), 7.22 (d, J = 8.6 Hz, 1H), 4.65 - 4.47 (m, 4H), 4.41 (d, J = 15.7 Hz, 1H), 4.07 (s, 4H), 3.97 (s, 3H), 3.93 (d, J = 11.1 Hz, 1H), 3.80 (dd, J = 11.0, 3.6 Hz, 1H), 3.74 (s, 2H), 3.66 (s, 2H), 2.60 (s, 3H), 2.53 (t, J = 7.4 Hz, 2H), 2.40 (t, J = 7.1 Hz, 2H), 2.28 - 2.20 (m, 1H), 2.11 - 2.02 (m, 1H), 2.01 - 1.92 (m, 2H), 1.87 (d, J = 13.6 Hz, 6H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₀H₆₃ClN₁₀O₇PS⁺ [M+H]⁺, 1013.4023; found, 1013.2012.

Compound Example 19: synthesis of (2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197149)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074013) was used to prepare SIAIS1197149 (white solid, 11.4 mg, 42%). ¹H NMR (500 MHz, MeOD) δ 10.02 (d, J = 2.9 Hz, 1H), 8.26 (s, 1H), 8.13 (m 1H), 7.80 - 7.63 (m, 3H), 7.60 - 7.49 (m, 6H), 7.25 (d, J = 8.8 Hz, 1H), 4.64 - 4.46 (m, 4H), 4.40 (dd, J = 15.7, 3.7 Hz, 1H), 4.10 (s, 4H), 3.97 (s, 3H), 3.90 (d, J = 11.1 Hz, 1H), 3.80 (dd, J = 11.0, 3.9 Hz, 1H), 3.76 (s, 2H), 3.68 (s, 2H), 2.61 (s, 3H), 2.59 - 2.48 (m, 2H), 2.38 - 2.32 (m, 2H), 2.27 - 2.21(m, 1H), 2.10 - 2.03 (m, 1H), 1.87 (d, J = 13.6 Hz, 6H), 1.77- 1.64 (m, 4H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₁H₆₅ClN₁₀O₇PS⁺ [M+H]⁺, 1027.4179; found, 1027.2037.

Compound Example 20: synthesis of (2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197151)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074014) was used to prepare SIAIS1197151 (white solid, 12.7 mg, 47%). ¹H NMR (500 MHz, MeOD) δ 10.03 (d, J = 1.2 Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.78 - 7.65 (m, 3H), 7.61 - 7.48 (m, 6H), 7.25 (d, J = 8.6 Hz, 1H), 4.63 (d, J = 7.6 Hz, 1H), 4.59 - 4.53 (m, 2H), 4.50 (s, 1H), 4.40 (dd, J = 15.8, 6.4 Hz, 1H), 4.11 (s, 4H), 3.98 (s, 3H), 3.90 (d, J = 11.0 Hz, 1H), 3.80 (dd, J = 11.0, 3.7 Hz, 1H), 3.77 - 3.60 (m, 4H), 2.61 (s, 3H), 2.52 (t, J = 7.5 Hz, 2H), 2.36 - 2.19 (m, 3H), 2.12 - 2.04 (m, 1H), 1.87 (d, J = 13.6 Hz, 6H), 1.72 - 1.57 (m, 4H), 1.47 - 1.29 (m, 2H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₂H₆₇ClN₁₀O₇PS⁺ [M+H]⁺, 1041.4336; found, 1041.2125.

Compound Example 21: synthesis of (2S,4R)-1-((S)-2-(8-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197153)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074015) was used to prepare SIAIS1197153 (white solid, 6.8 mg, 25%). ¹H NMR (500 MHz, MeOD) δ 9.99 (d, J = 4.4 Hz, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.74 (dd, J = 13.0, 7.6 Hz, 1H), 7.66 (t, J = 7.5 Hz, 2H), 7.60 - 7.46 (m, 5H), 7.40 (s, 1H), 7.14 (d, J = 8.7 Hz, 1H), 4.63 (d, J = 6.1 Hz, 1H), 4.60 -- 4.52 (m, 2H), 4.50 (s, 1H), 4.40 (dd, J = 15.8, 7.7 Hz, 1H), 4.05 (s, 4H), 3.96 (s, 3H), 3.91 (d, J = 11.0 Hz, 1H), 3.80 (dd, J = 11.1, 3.7 Hz, 1H), 3.68 (s, 2H), 3.62 (s, 2H), 2.61 (s, 3H), 2.51 (t, J = 7.5 Hz, 2H), 2.40 - 2.17 (m, 3H), 2.11 - 2.03 (m, 1H), 1.87 (d, J = 13.5 Hz, 6H), 1.70 - 1.55 (m, 4H), 1.45 - 1.30 (m, 4H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₃H₆₉ClN₁₀O₇PS⁺ [M+H]⁺, 1055.4492; found, 1055.2208.

Compound Example 22: synthesis of (2S,4R)-1-((S)-2-(9-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197155)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074016) was used to prepare SIAIS1197155 (white solid, 8.3 mg, 31%). ¹H NMR (500 MHz, MeOD) δ 9.96 (s, 1H), 8.19 (d, J = 14.1 Hz, 2H), 7.73 (dd, J = 14.0, 6.8 Hz, 1H), 7.67 - 7.45 (m, 6H), 7.31 (s, 1H), 7.07 (d, J = 8.7 Hz, 1H), 4.64 (s, 1H), 4.60 - 4.52 (m, 2H), 4.50 (s, 1H), 4.41 (d, J = 15.8 Hz, 1H), 4.00 (s, 4H), 3.95 (s, 3H), 3.91 (d, J = 11.1 Hz, 1H), 3.80 (dd, J = 11.0, 3.8 Hz, 1H), 3.63 (s, 2H), 3.57 (s, 2H), 2.60 (s, 3H), 2.50 (t, J = 7.6 Hz, 2H), 2.37 - 2.18 (m, 3H), 2.11 - 2.03 (m, 1H), 1.87 (d, J = 13.6 Hz, 6H), 1.70 - 1.55 (m, 4H), 1.45 - 1.30 (m, 6H), 1.02 (s, 9H). HRMS (ESI) calcd for C₅₄H₇₁ClN₁₀O₇PS⁺ [M+H]⁺, 1069.4649; found, 1069.2386.

Compound Example 23: synthesis of (2S,4R)-1-((S)-2-(10-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS1197157)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue A and intermediate LM (SIAIS074019) was used to prepare SIAIS1197157 (white solid, 10.6 mg, 39%). ¹H NMR (500 MHz, MeOD) δ 9.56 (d, J = 4.2 Hz, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.70 (s, 1H), 7.62 - 7.30 (m, 6H), 6.86 (s, 1H), 6.71 (s, 1H), 4.64 (d, J = 3.5 Hz, 1H), 4.60 - 4.47 (m, 3H), 4.39 (dd, J = 15.7, 3.2 Hz, 1H), 4.00 - 3.69 (m, 9H), 3.36 (s, 4H), 2.55 (d, J = 3.8 Hz, 3H), 2.51 - 2.40 (m, 2H), 2.38 - 2.18 (m, 3H), 2.12 - 2.02 (m, 1H), 1.89 (dd, J = 13.6, 3.5 Hz, 6H), 1.62 (s, 4H), 1.35 (s, 8H), 1.03 (t, J = 5.8 Hz, 9H). HRMS (ESI) calcd for C₅₅H₇₃ClN₁₀O₇PS⁺ [M+H]⁺, 1083.4805; found, 1083.2486.

Compound Example 24: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propenamide. (SIAIS151113)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151001) was used to prepare SIAIS151113 (yellow solid, 10.4 mg, 60%). ¹H NMR (500 MHz, MeOD) δ 8.29 (dd, J = 8.1, 3.8 Hz, 1H), 8.13 (s, 1H), 7.74 - 7.67 (m, 2H), 7.63 - 7.59 (m, 1H), 7.55 (dd, J = 8.6, 7.1 Hz, 1H), 7.41 - 7.31 (m, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 7.00 (d, J = 1.9 Hz, 1H), 6.81 (dd, J = 8.8, 2.4 Hz, 1H), 5.03 (dd, J = 12.5, 5.5 Hz, 1H), 4.10 - 3.85 (m, 2H), 3.92 (s, 3H), 3.79 (t, J = 5.9 Hz, 2H), 3.71 (t, J = 5.1 Hz, 2H), 3.68 - 3.64 (m, 2H), 3.50 (t, J = 5.0 Hz, 2H), 2.93 - 2.61 (m, 4H), 2.48 (t, J = 5.9 Hz, 2H), 2.10 - 2.01 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.83 - 1.75 (m, 2H). HRMS (ESI) calcd for C₄₂H₄₈ClN₉O₈P⁺ [M+H]⁺: 872.3047, found, 872.2645.

Compound Example 25: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propenamide. (SIAIS151114)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151004) was used to prepare SIAIS151114 (yellow solid, 9.8 mg, 53%). ¹H NMR (500 MHz, MeOD) δ 8.29 (dd, J = 7.5, 3.5 Hz, 1H), 8.13 (s, 1H), 7.72 - 7.67 (m, 2H), 7.62 - 7.59 (m, 1H), 7.52 (dd, J = 8.5, 7.1 Hz, 1H), 7.41 - 7.37 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 6.9 Hz, 1H), 6.99 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.04 (dd, J = 12.6, 5.5 Hz, 1H), 4.00 - 3.94 (m, 1H), 3.90 (s, 3H), 3.76 (t, J = 6.1 Hz, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.70 - 3.62 (m, 8H), 3.48 (t, J = 5.3 Hz, 2H), 2.87 - 2.80 (m, 1H), 2.75 - 2.67 (m, 2H), 2.46 (t, J = 6.0 Hz, 2H), 2.13 - 2.07 (m, 3H), 1.88 (s, 3H), 1.86 (s, 3H), 1.84 - 1.77 (m, 2H). HRMS (ESI) calcd for C₄₄H₅₂ClN₉O₉P⁺ [M+H]⁺: 916.3309, found, 916.2857.

Compound Example 26: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propenamide. (SIAIS151115)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151005) was used to prepare SIAIS151115 (yellow solid, 16.8 mg, 87%). ¹H NMR (500 MHz, MeOD) δ 8.30 (dd, J = 7.5, 3.5 Hz, 1H), 8.12 (s, 1H), 7.73 - 7.66 (m, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (dd, J = 8.5, 7.1 Hz, 1H), 7.39 (t, J = 7.1 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 7.00 (s, 1H), 6.81 (d, J = 6.9 Hz, 1H), 5.04 (dd, J = 12.7, 5.5 Hz, 1H), 4.02 - 3.96 (m, 1H), 3.90 (s, 3H), 3.75 - 3.67 (m, 7H), 3.65 (s, 3H), 3.64 - 3.63 (m, 3H), 3.61 - 3.59 (m, 2H), 3.48 (t, J = 5.2 Hz, 2H), 3.38 - 3.35 (m, 1H), 2.89 - 2.81 (m, 1H), 2.76 - 2.67 (m, 2H), 2.45 (t, J = 6.0 Hz, 2H), 2.16 - 2.07 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.84 - 1.78 (m, 2H). HRMS (ESI) calcd for C₄₆H₅₆ClN₉O₁₀P⁺ [M+H]⁺: 960.3571, found, 960.3920.

Compound Example 27: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-amide. (SIAIS151116)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151006) was used to prepare SIAIS151116 (yellow solid, 13.5 mg, 67%). ¹H NMR (500 MHz, MeOD) δ 8.30 (dd, J = 7.5, 3.5 Hz, 1H), 8.12 (s, 1H), 7.75 - 7.66 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.51 (dd, J = 8.5, 7.1 Hz, 1H), 7.38 (dd, J = 7.0, 6.0 Hz, 1H), 7.05 - 6.99 (m, 3H), 6.82 (d, J = 8.2 Hz, 1H), 5.03 (dd, J = 12.7, 5.5 Hz, 1H), 4.03 - 3.96 (m, 1H), 3.90 (s, 3H), 3.75 - 3.68 (m, 6H), 3.65 - 3.59 (m, 12H), 3.45 (t, J = 5.3 Hz, 2H), 3.39 - 3.34 (m, 2H), 2.88 - 2.81 (m, 1H), 2.77 - 2.62 (m, 2H), 2.45 (t, J = 6.0 Hz, 2H), 2.16 - 2.12 (m, 2H), 2.11 - 2.06 (m, 1H), 1.88 (s, 3H), 1.85 (s, 3H), 1.85 - 1.78 (m, 2H). HRMS (ESI) calcd for C₄₈H₆₀ClN₉O₁₁P⁺ [M+H]⁺: 1004.3833, found, 1004.4184.

Compound Example 28: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-amide. (SIAIS151117)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151007) was used to prepare SIAIS151117 (yellow solid, 15.8 mg, 75%). ¹H NMR (500 MHz, MeOD) δ 8.24 (dd, J = 7.5, 3.5 Hz, 1H), 8.16 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.69 (ddd, J = 13.9, 7.7, 1.4 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.52 (dd, J = 8.5, 7.1 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.16 - 7.11 (m, 1H), 7.03 (dd, J = 15.1, 7.8 Hz, 2H), 6.92 (d, J = 8.7 Hz, 1H), 5.03 (dd, J = 12.8, 5.5 Hz, 1H), 4.06 - 4.00 (m, 1H), 3.92 (s, 3H), 3.75 - 3.71 (m, 4H), 3.69 (t, J = 5.3 Hz, 2H), 3.64 - 3.60 (m, 16H), 3.53 - 3.48 (m, 2H), 3.45 (t, J = 5.3 Hz, 2H), 2.88 - 2.80 (m, 1H), 2.75 - 2.64 (m, 2H), 2.46 (t, J = 6.0 Hz, 2H), 2.20 - 2.17 (m, 2H), 2.11 - 2.06 (m, 1H), 1.95 - 1.89 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H). HRMS (ESI) calcd for C₅₀H₆₄ClN₉O₁₂P⁺ [M+H]⁺: 1049.5400, found, 1049.4482.

Compound Example 29: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide. (SIAIS151120)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151025) was used to prepare SIAIS151120 (yellow solid, 11.1 mg, 68%). ¹H NMR (500 MHz, MeOD) δ 8.31 (dd, J = 7.5, 3.5 Hz, 1H), 8.10 (s, 1H), 7.72-7.66 (m, 2H), 7.62 - 7.57 (m, 2H), 7.40 - 7.36 (m, 1H), 7.13 (d, J = 7.0 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 5.08 (dd, J = 12.6, 5.5 Hz, 1H), 4.07 - 4.01 (m, 3H), 3.90 (s, 3H), 3.74-3.69 (m, 2H), 3.38-3.31 (m, 2H), 2.88 - 2.83 (m, 1H), 2.78 - 2.76 (m, 1H), 2.75 - 2.71 (m, 1H), 2.15 - 2.08 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.85 - 1.78 (m, 2H). HRMS (ESI) calcd for C₃₉H₄₂ClN₉O₇P⁺ [M+H]⁺: 814.2628, found, 814.3211.

Compound Example 30: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propenamide. (SIAIS151121)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151026) was used to prepare SIAIS151121 (yellow solid, 14 mg, 85%). ¹H NMR (500 MHz, MeOD) δ 8.29 (dd, J = 7.5, 3.5 Hz, 1H), 8.12 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.69 (ddd, J = 13.9, 7.8, 1.4 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.41 - 7.36 (m, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 6.9 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 5.03 (dd, J = 12.4, 5.5 Hz, 1H), 4.02 - 3.96 (m, 1H), 3.92 (s, 3H), 3.71 - 3.67 (m, 4H), 3.40 - 3.34 (m, 2H), 2.86 - 2.79 (m, 1H), 2.75 - 2.65 (m, 2H), 2.56 (dd, J = 6.9, 5.3 Hz, 2H), 2.12 - 2.05 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.81 - 1.72 (m, 2H). HRMS (ESI) calcd for C₄₀H₄₄ClN₉O₇P⁺ [M+H]⁺: 828.2784, found, 828.3370.

Compound Example 31: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanamide. (SIAIS151118)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151019) was used to prepare SIAIS151118 (yellow solid, 13.2 mg, 78%). ¹H NMR (500 MHz, MeOD) δ 8.30 (dd, J = 7.5, 3.5 Hz, 1H), 8.11 (s, 1H), 7.75 - 7.73 (m, 1H), 7.69 (ddd, J = 13.9, 7.7, 1.4 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.56 (dd, J = 9.0, 7.5 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 6.8 Hz, 1H), 6.99 (s, 1H), 6.81 (d, J = 8.4 Hz, 1H), 5.06 (dd, J = 12.6, 5.5 Hz, 1H), 3.96 - 3.89 (m, 1H), 3.91 (s, 3H), 3.71 - 3.68 (m, 2H), 3.41 (t, J = 6.7 Hz, 2H), 3.37 - 3.33 (m, 2H), 2.89 - 2.81 (m, 1H), 2.77 - 2.69 (m, 2H), 2.34 (t, J = 7.0 Hz, 2H), 2.14 - 2.05 (m, 3H), 2.03 - 1.97 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.81 - 1.72 (m, 2H). HRMS (ESI) calcd for C₄₁H₄₆ClN₉O₇P⁺ [M+H]⁺: 842.2941, found, 842.3294.

Compound Example 32: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide. (SIAIS151119)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151020) was used to prepare SIAIS151119 (yellow solid, 12 mg, 70%). ¹H NMR (500 MHz, MeOD) δ 8.30 (dd, J = 7.5, 3.5 Hz, 1H), 8.11 (s, 1H), 7.71 - 7.66 (m, 2H), 7.61 (t, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.6, 7.1 Hz, 1H), 7.41 - 7.37 (m, 1H), 7.05 (dd, J = 9.8, 7.8 Hz, 2H), 7.00 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 8.8, 2.3 Hz, 1H), 5.05 (dd, J = 12.5, 5.5 Hz, 1H), 4.00 - 3.94 (m, 1H), 3.92 (s, 3H), 3.75 - 3.70 (m, 2H), 3.39 - 3.33 (m, 4H), 2.88 - 2.80 (m, 1H), 2.76 - 2.66 (m, 2H), 2.28 (t, J = 7.1 Hz, 2H), 2.15 - 2.08 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.83 - 1.68 (m, 6H). HRMS (ESI) calcd for C₄₂H₄₈ClN₉O₇P⁺ [M+H]⁺: 856.3097, found, 856.3403.

Compound Example 33: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide. (SIAIS151122)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151027) was used to prepare SIAIS151122 (yellow solid, 4.5 mg, 30%). ¹H NMR (500 MHz, MeOD) δ 8.32 (dd, J = 7.5, 3.5 Hz, 1H), 8.10 (s, 1H), 7.69 (ddd, J = 14.0, 7.8, 1.4 Hz, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.55 (dd, J = 8.6, 7.1 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.05 (dd, J = 10.9, 7.7 Hz, 2H), 6.96 (s, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.04 (dd, J = 12.5, 5.5 Hz, 1H), 3.97 - 3.93 (m, 1H), 3.91 (s, 3H), 3.72 - 3.68 (m, 2H), 3.36 (t, J = 6.8 Hz, 2H), 3.30 - 3.23 (m, 2H), 2.85 - 2.76 (m, 1H), 2.75 - 2.65 (m, 2H), 2.24 (t, J = 7.2 Hz, 2H), 2.11 - 2.05 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.79 - 1.73 (m, 2H), 1.73 - 1.67 (m, 4H), 1.51 - 1.43 (m, 2H). HRMS (ESI) calcd for C₄₃H₅₀ClN₉O₇P⁺ [M+H]⁺: 870.3254, found, 870.3881.

Compound Example 34: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanamide. (SIAIS151123)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151086) was used to prepare SIAIS151123 (yellow solid, 12.3 mg, 70%). ¹H NMR (500 MHz, MeOD) δ 8.30 (dd, J = 7.5, 3.5 Hz, 1H), 8.11 (s, 1H), 7.75 - 7.66 (m, 2H), 7.61 (t, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.6, 7.1 Hz, 1H), 7.41 - 7.37 (m, 1H), 7.04 (t, J = 7.5 Hz, 2H), 7.00 (s, 1H) 6.82 (d, J = 7.7 Hz, 1H), 5.05 (dd, J = 12.5, 5.5 Hz, 1H), 4.01 - 3.93 (m, 1H), 3.92 (s, 3H), 3.72 - 3.70 (m, 2H), 3.37 - 3.32 (m, 4H), 2.89 - 2.79 (m, 1H), 2.76 - 2.69 (m, 2H), 2.22 (t, J = 7.4 Hz, 2H), 2.14 - 2.05 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.84 - 1.76 (m, 2H), 1.72 - 1.64 (m, 4H), 1.50 - 1.40 (m, 4H). HRMS (ESI) calcd for C₄₄H₅₂ClN₉O₇P⁺ [M+H]⁺: 884.3410, found, 884.3420.

Compound Example 35: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)acetamide. (SIAIS219151)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS 1204057) was used to prepare SIAIS219151 (yellow solid, 7.2 mg, 45%). ¹H NMR (500 MHz, MeOD) δ 8.19 (s, 2H), 7.72 (dd, J = 13.7, 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.17 (d, J = 7.5 Hz, 1H), 6.99 (s, 1H), 6.72 (d, J = 8.1 Hz, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 16.8 Hz, 1H), 4.39 (d, J = 16.9 Hz, 1H), 4.15 (s, 1H), 3.95 (s, 3H), 3.73 - 3.68 (m, 2H), 3.63 - 3.50 (m, 4H), 2.97-2.90 (m, 1H), 2.85 - 2.77 (m, 1H), 2.55-2.46 (m, 1H), 2.22-2.15 (m, 3H), 2.00 (s, 2H), 1.86 (d, J = 13.5 Hz, 6H). HRMS (ESI) calcd for C39H44ClN9O7P+ [M+H]⁺: 800.2835, found, 800.2831.

Compound Example 36: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanamide. (SIAIS219128)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS 1204085) was used to prepare SIAIS219128 (yellow solid, 10 mg, 40%). ¹H NMR (500 MHz, MeOD) δ 8.24 (s, 1H), 8.12 (s, 1H), 7.79 - 7.71 (m, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.1 Hz, 1H), 7.44 (s, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.21 - 7.15 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 5.20 (dd, J = 13.3, 5.0 Hz, 1H), 4.44 (d, J = 17.0 Hz, 1H), 4.37 (d, J = 17.0 Hz, 1H), 3.98 (s, 4H), 3.82 - 3.62 (m, 4H), 3.41-3.37 (m, 2H), 3.01 - 2.89 (m, 1H), 2.83 (d, J = 16.7 Hz, 1H), 2.58 - 2.48 (m, 1H), 2.41 (t, J = 6.7 Hz, 2H), 2.28 - 2.13 (m, 2H), 2.07-1.96 (m, 4H), 1.87 (d, J = 13.5 Hz, 6H), 1.77 (d, J = 14.2 Hz, 1H). HRMS (ESI) calcd for C₄₁H₄₈ClN₉O₆P⁺ [M+H]⁺: 828.3148, found, 828.3141.

Compound Example 37: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoi soindolin-4-yl)amino)pentanamide (SIAIS219152)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS1210133) was used to prepare SIAIS219152 (yellow solid, 8.0 mg, 47%). ¹H NMR (500 MHz, MeOD) δ 8.25 (s, 1H), 8.13 (s, 1H), 7.80 - 7.71 (m, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.55 - 7.41 (m, 3H), 7.37 - 7.25 (m, 1H), 7.22-7.17 (m, 1H), 7.14-7.08 (m, 1H), 5.17 (dd, J = 13.2, 5.1 Hz, 1H), 4.53 - 4.38 (m, 2H), 4.08 (s, 1H), 3.99 (s, 3H), 3.73 (s, 4H), 3.35-3.32 (m, 2H), 2.93-2.90 (m, 1H), 2.83-2.81 (m, 1H), 2.59 - 2.46 (m, 1H), 2.32 (s, 2H), 2.23-2.07 (m, 5H), 1.87 (d, J = 13.6 Hz, 6H), 1.81 - 1.71 (m, 4H). HRMS (ESI) calcd for C₄₂H₅₀ClN₉O₆P⁺ [M+H]⁺: 842.3305, found, 842.3301.

Compound Example 38: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanamide. (SIAIS219153)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS1204061) was used to prepare SIAIS219153 (yellow solid, 8.2 mg, 48%). ¹H NMR (500 MHz, MeOD) δ 8.25 (s, 1H), 8.14 (s, 1H), 7.80 - 7.71 (m, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.54 - 7.40 (m, 3H), 7.31-7.25 (m 1H), 7.21-7.17 (m, 1H), 7.15 - 7.03 (m, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.48-4.38 (m, 2H), 4.06 (s, 1H), 3.99 (s, 3H), 3.72 (s, 4H), 3.33-3.31 (m, 2H), 2.93-2.90 (m, 1H), 2.82-2.81 (m, 1H), 2.58 - 2.47 (m, 1H), 2.27 (t, J = 6.7 Hz, 2H), 2.24-2.16 (m, 2H), 2.05-2.04 (m, 3H), 1.87 (d, J = 13.5 Hz, 6H), 1.76 - 1.68 (m, 4H), 1.52-1.45 (m, 2H). HRMS (ESI) calcd for C₄₃H₅₂ClN₉O₆P⁺ [M+H]⁺: 856.3461, found, 856.3449.

Compound Example 39: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptanamide. (SIAIS219154)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS 1204063) was used to prepare SIAIS219154 (yellow solid, 7.9 mg, 45%). ¹H NMR (500 MHz, MeOD) δ 8.22 (s, 1H), 8.17 (s, 1H), 7.79 - 7.70 (m, 2H), 7.66 (t, J = 7.8 Hz, 1H), 7.47 (t, J = 7.1 Hz, 1H), 7.39 (dd, J = 16.2, 8.4 Hz, 2H), 7.20 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.42 (d, J = 17.0 Hz, 1H), 4.37 (d, J = 17.0 Hz, 1H), 4.06 (t, J = 10.9 Hz, 1H), 3.98 (s, 3H), 3.69-3.62 (m, 4H), 3.30 - 3.26 (m, 2H), 2.99 - 2.89 (m, 1H), 2.85 - 2.76 (m, 1H), 2.58 - 2.46 (m, 1H), 2.26-2.15 (m, 5H), 2.04-2.00 (m, 2H), 1.87 (d, J = 13.5 Hz, 6H), 1.74 - 1.65 (m, 4H), 1.51-1.46 (m, 2H), 1.44-1.40 (m, 2H). HRMS (ESI) calcd for C₄₄H₅₄ClN₉O₆P⁺ [M+H]⁺: 870.3618, found, 870.3611.

Compound Example 40: synthesis of (2S,4R)-1-((S)-2-(2-(2-(2-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151128)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS 151010) was used to prepare SIAIS151128 (white solid, 14.7 mg, 68%). ¹H NMR (500 MHz, MeOD) δ 8.92 (s, 1H), 8.30 (dd, J = 8.0, 4.1 Hz, 1H), 8.11 (s, 1H), 7.71 - 7.64 (m, 2H), 7.61 - 7.57 (m, 1H), 7.43 - 7.38 (m, 5H), 7.00 (s, 1H), 6.82 (dd, J = 8.5, 2.0 Hz, 1H), 4.72 (s, 1H), 4.59 - 4.56 (m, 1H), 4.53 - 4.46 (m, 2H), 4.38 (d, J = 15.7 Hz, 1H), 4.13 - 4.02 (m, 5H), 3.91 - 3.90 (m, 1H), 3.90 (s, 3H), 3.85 - 3.65 (m, 8H), 3.37 - 3.34 (m, 1H), 2.46 (s, 3H), 2.28 - 2.23 (m, 1H), 2.15 - 2.07 (m, 3H), 1.99 - 1.91 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₂H₆₇ClN₁₀O₉PS⁺ [M+H]⁺: 1073.4234, found, 1073.4229.

Compound Example 41: synthesis of (2S,4R)-1-((S)-2-(3-(2-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151124)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151002) was used to prepare SIAIS151124 (white solid, 6.1 mg, 28%). ¹H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.30 (dd, J = 7.5, 3.5 Hz, 1H), 8.12 (s, 1H), 7.73 - 7.66 (m, 2H), 7.63 - 7.59 (m, 1H), 7.47 - 7.45 (m, 2H), 7.43 - 7.38 (m, 3H), 7.03 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 8.8, 2.4 Hz, 1H), 4.66 (s, 1H), 4.60 - 4.54 (m, 1H), 4.51 - 4.47 (m, 2H), 4.39 - 4.34 (m, 1H), 4.03 - 3.96 (m, 1H), 3.91 - 3.87 (m, 1H), 3.92 (s, 3H), 3.80 (dd, J = 11.0, 3.8 Hz, 1H), 3.75 - 3.70 (m, 6H), 3.64 - 3.60 (m, 4H), 3.40 - 3.34 (m, 2H), 2.61 - 2.53 (m, 1H), 2.49 - 2.44 (m, 3H), 2.47 (s, 3H), 2.25 - 2.20 (m, 1H), 2.16 - 2.05 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.84 - 1.78 (m, 2H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₄H₇₁ClN₁₀O₉PS⁺ [M+H]⁺: 1101.4547, found, 1101.4558.

Compound Example 42: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-16-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151125)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151003) was used to prepare SIAIS151125 (white solid, 13.2 mg, 58%). ¹H NMR (500 MHz, MeOD) δ 8.94 (s, 1H), 8.29 (dd, J = 7.5, 3.5 Hz, 1H), 8.12 (s, 1H), 7.73 - 7.67 (m, 2H), 7.62 - 7.58 (m, 1H), 7.47 - 7.44 (m, 2H), 7.43 - 7.37 (m, 3H), 7.04 (s, 1H), 6.86 (d, J = 8.6 Hz, 1H), 4.65 (s, 1H), 4.59 - 4.50 (m, 2H), 4.50 - 4.47 (m, 1H), 4.38 - 4.33 (m, 1H), 4.03 - 3.97 (m, 1H), 3.92 (s, 3H), 3.89 - 3.86 (m, 1H), 3.80 (dd, J = 10.9, 3.9 Hz, 1H), 3.76 - 3.70 (m, 6H), 3.64 - 3.58 (m, 9H), 3.44 - 3.35 (m, 2H), 2.60 - 2.54 (m, 1H), 2.50 - 2.44 (m, 3H), 2.47 (s, 3H), 2.24 - 2.20 (m, 1H), 2.17-2.13 (m, 2H), 2.10 - 2.05 (m, 1H), 1.88 (s, 3H), 1.86 - 1.80 (m, 2H), 1.85 (s, 3H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₆H₇₅ClN₁₀O₁₀PS⁺ [M+H]⁺: 1145.4809, found, 1145.4807.

Compound Example 43: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N16-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13-tetraoxahexadecanediamide. (SIAIS151126)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS 151008) was used to prepare SIAIS151126 (white solid, 13.0 mg, 55%). ¹H NMR (500 MHz, MeOD) δ 8.99 (s, 1H), 8.25 (dd, J = 8.1, 4.0 Hz, 1H), 8.16 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 13.9, 7.7 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.48 - 7.46 (m, 2H), 7.44 - 7.41 (m, 3H), 7.15 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 8.8, 2.5 Hz, 1H), 4.64 (s, 1H), 4.59 - 4.51 (m, 2H), 4.50 - 4.47 (m, 1H), 4.36 (d, J = 15.5 Hz, 1H), 4.08 - 4.01 (m, 1H), 3.93 (s, 3H), 3.90 - 3.87 (m, 1H), 3.79 (dd, J = 10.9, 3.7 Hz, 1H), 3.76 - 3.71 (m, 6H), 3.62 - 3.60 (m, 12H), 3.50 (t, J = 11.1 Hz, 2H), 2.58 - 2.53 (m, 1H), 2.49 - 2.45 (m, 3H), 2.48 (s, 3H), 2.24-2.16 (m, 3H), 2.11 - 2.05 (m, 1H), 1.94 - 1.90 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₉ClN₁₀O₁₁PS⁺ [M+H]⁺: 1189.5071, found, 1189.5091.

Compound Example 44: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N19-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13,16-pentaoxanonadecanediamide. (SIAIS151127)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS151009) was used to prepare SIAIS151127 (white solid, 19.5 mg, 79%). ¹H NMR (500 MHz, MeOD) δ 9.05 (s, 1H), 8.23 (dd, J = 8.0, 4.1 Hz, 1H), 8.17 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.71 (ddd, J = 13.9, 7.8, 1.4 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.50 - 7.46 (m, 2H), 7.44 - 7.40 (m, 3H), 7.19 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.8, 2.5 Hz, 1H), 4.64 (s, 1H), 4.58 - 4.51 (m, 2H), 4.51 - 4.48 (m, 1H), 4.36 (d, J = 15.6 Hz, 1H), 4.09 - 4.03 (m, 1H), 3.94 (s, 3H), 3.90 - 3.87 (m, 1H), 3.80 (dd, J = 11.0, 3.9 Hz, 1H), 3.76 - 3.69 (m, 6H), 3.62 - 3.60 (m, 16H), 3.54 (t, J = 12.0 Hz, 2H), 2.59 - 2.54 (m, 1H), 2.50 - 2.45 (m, 3H), 2.49 (s, 3H), 2.24 - 2.18 (m, 3H), 2.11-2.05 (m, 1H), 1.98 - 1.91 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₀H₈₃ClN₁₀O₁₂PS⁺ [M+H]⁺: 1233.5333, found, 1233.5335.

Compound Example 45: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)succinamide. (SIAIS164143)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074011) was used to prepare SIAIS164143 (white solid, 12.8 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 9.95 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.78 - 7.73 (m, 2H), 7.68 (t, J = 7.5 Hz, 1H), 7.60 - 7.50 (m, 6H), 7.29 (d, J = 8.2 Hz, 1H), 4.62 - 4.47 (m, 4H), 4.41 (d, J = 15.6 Hz, 1H), 4.19-4.11 (m, 1H), 4.00 (s, 3H), 3.91 - 3.89 (m, 1H), 3.81 - 3.78 (m, 5H), 2.67-2.53 (m, 4H), 2.59 (s, 3H), 2.31 - 2.15 (m, 5H), 2.11 - 2.04 (m, 1H), 1.88 (s, 3H), 1.86 (s, 3H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₀H₆₃ClN₁₀O₇PS⁺ [M+H]⁺: 1013.4023, found, 1013.3452.

Compound Example 46: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide. (SIAIS164144)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074012) was used to prepare SIAIS164144 (white solid, 12.2 mg, 59%). ¹H NMR (500 MHz, MeOD) δ 9.96 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.78 - 7.73 (m, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.61 - 7.56 (m, 3H), 7.55 - 7.49 (m, 3H), 7.30 (d, J = 8.7 Hz, 1H), 4.64 (s, 1H), 4.69 - 4.51 (m, 3H), 4.45 - 4.40 (m, 1H), 4.20 - 4.12 (m, 1H), 4.00 (s, 3H), 3.93 (d, J = 11.2 Hz, 1H), 3.86 - 3.73 (m, 5H), 2.60 (s, 3H), 2.38-2.17 (m, 9H), 2.11 - 2.05 (m, 1H), 1.96 - 1.91 (m, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₁H₆₅ClN₁₀O₇PS⁺ [M+H]⁺: 1027.4179, found, 1027.3585.

Compound Example 47: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)adipamide. (SIAIS164145)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074013) was used to prepare SIAIS164145 (white solid, 13.1 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 10.01 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.78 - 7.74 (m, 2H), 7.69 (t, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.59 - 7.57 (m, 2H), 7.55 - 7.50 (m, 3H), 7.32 (d, J = 6.9 Hz, 1H), 4.64 (s, 1H), 4.61 - 4.47 (m, 3H), 4.43 - 4.39 (m, 1H), 4.21 - 4.13 (m, 1H), 4.00 (s, 3H), 3.92 (d, J = 11.1 Hz, 1H), 3.85 - 3.71 (m, 5H), 2.61 (s, 3H), 2.36 - 2.17 (m, 9H), 2.10 - 2.04 (m, 1H), 1.88 (s, 3H), 1.86 (s, 3H), 1.70 - 1.62 (m, 4H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₂H₆₇ClN₁₀O₇PS⁺ [M+H]⁺: 1041.4336, found, 1041.3764.

Compound Example 48: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N7-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)heptanediamide. (SIAIS164146)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074014) was used to prepare SIAIS164146 (white solid, 12.3 mg, 58%). ¹H NMR (500 MHz, MeOD) δ 9.97 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.77 - 7.73 (m, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.61 - 7.50 (m, 6H), 7.29 (d, J = 8.7 Hz, 1H), 4.64 (s, 1H), 4.61 - 4.48 (m, 3H), 4.44-4.38 (m, 1H), 4.18-4.12 (m, 1H), 4.00 (s, 3H), 3.91 (d, J = 11.1 Hz, 1H), 3.85 - 3.70 (m, 5H), 2.60 (s, 3H), 2.36 - 2.15 (m, 9H), 2.10 - 2.05 (m, 1H), 1.88 (s, 3H), 1.85 (s, 3H), 1.69 - 1.61 (m, 4H), 1.42 - 1.33 (m, 2H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₃H₆₉ClN₁₀O₇PS⁺ [M+H]⁺: 1055.4492, found, 1055.3854.

Compound Example 49: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)octanediamide. (SIAIS164147)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074015) was used to prepare SIAIS164147 (white solid, 14.8 mg, 69%). ¹H NMR (500 MHz, MeOD) δ 9.91 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.77 - 7.73 (m, 2H), 7.69 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.58 - 7.51 (m, 5H), 7.31 (d, J = 8.7 Hz, 1H), 4.64 (s, 1H), 4.60 - 4.49 (m, 3H), 4.43 - 4.38 (m, 1H), 4.20 - 4.13 (m, 1H), 4.00 (s, 3H), 3.92 (d, J = 11.1 Hz, 1H), 3.86 - 3.75 (m, 5H), 2.60 (s, 3H), 2.33 - 2.18 (m, 9H), 2.11 - 2.05 (m, 1H), 1.88 (s, 3H), 1.85 (s, 3H), 1.68 - 1.59 (m, 4H), 1.41 - 1.34 (m, 4H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₄H₇₁ClN₁₀O₇PS⁺ [M+H]⁺: 1069.4649, found, 1069.4001.

Compound Example 50: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N9-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)nonanediamide. (SIAIS164148)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074016) was used to prepare SIAIS164148 (white solid, 12.8 mg, 59%). ¹H NMR (500 MHz, MeOD) δ 10.01 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.78 - 7.73 (m, 2H), 7.69 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.60 - 7.57 (m, 2H), 7.55 - 7.49 (m, 3H), 7.31 (d, J = 8.8 Hz, 1H), 4.64 (s, 1H), 4.60 - 4.49 (m, 3H), 4.44 - 4.38 (m, 1H), 4.21 - 4.13 (m, 1H), 4.00 (s, 3H), 3.91 (d, J = 11.1 Hz, 1H), 3.85 - 2.73 (m, 5H), 2.61 (s, 3H), 2.33 - 2.18 (m, 9H), 2.10 - 2.04 (m, 1H), 1.88 (s, 3H), 1.86 (s, 3H), 1.66 - 1.59 (m, 4H), 1.36 (s, 6H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₅H₇₃ClN₁₀O₇PS⁺ [M+H]⁺: 1083.4805, found, 1083.4133.

Compound Example 51: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamide. (SIAIS164149)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074019) was used to prepare SIAIS164149 (white solid, 10.2 mg, 46%). ¹H NMR (500 MHz, MeOD) δ 10.02 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.79 - 7.73 (m, 2H), 7.69 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.54 - 7.50 (m, 3H), 7.32 (d, J = 8.6 Hz, 1H), 4.64 (s, 1H), 4.60 - 4.49 (m, 3H), 4.44 - 4.38 (m, 1H), 4.20-4.14 (m, 1H), 4.00 (s, 3H), 3.91 (d, J = 11.2 Hz, 1H), 3.81 (dd, J = 10.9, 3.9 Hz, 5H), 2.61 (s, 3H), 2.33 - 2.18 (m, 9H), 2.10 - 2.05 (m, 1H), 1.88 (s, 3H), 1.86 (s, 3H), 1.67 - 1.57 (m, 4H), 1.35 (s, 9H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₆H₇₅ClN₁₀O₇PS⁺ [M+H]⁺: 1097.4962, found, 1097.4296.

Compound Example 52: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N11-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)undecanediamide. (SIAIS1210117)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS074020) was used to prepare SIAIS1210117 (white solid, 10.6 mg, 48%). ¹H NMR (500 MHz, MeOD) δ 8.94 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 7.72 (dd, J = 14.0, 6.7 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.3 Hz, 3H), 7.11 (s, 1H), 6.91 (d, J = 7.8 Hz, 1H), 4.66 (s, 1H), 4.62 - 4.55 (m, 2H), 4.58 - 4.50 (m, 2H), 4.41 - 4.36 (m, 1H), 3.95 (s, 3H), 3.92 (d, J = 11.1 Hz, 1H), 3.82 (dd, J = 11.0, 3.9 Hz, 1H), 3.75 (d, J = 12.6 Hz, 2H), 3.47 - 3.40 (m, 2H), 2.49 (s, 3H), 2.26 - 2.21 (m, 4H), 2.17 (d, J = 12.5 Hz, 2H), 1.90 - 1.85 (m, 8H), 1.68 - 1.57 (m, 6H), 1.39 - 1.33 (m, 10H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₇ClN₁₀O₇PS⁺ [M+H]⁺: 1111.5118, found, 1111.5109.

Comparative Example 53: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N11-((S)-1-((2S,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)undecanediamide. (SIAIS219050)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS219048) was used to prepare SIAIS219050 (white solid, 8.2 mg, 37%). ¹H NMR (500 MHz, MeOD) δ 9.34 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.82 - 7.71 (m, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.50 - 7.45 (m, 6H), 7.18 (d, J = 8.6 Hz, 1H), 4.56 - 4.50 (m, 3H), 4.45 - 4.36 (m, 2H), 4.14-4.10 (m, 1H), 4.04 (dd, J = 10.5, 5.1 Hz, 1H), 3.98 (s, 3H), 3.75-3.68 (m, 6H), 2.53 (s, 3H), 2.50 - 2.40 (m, 1H), 2.34 - 2.20 (m, 8H), 2.13-2.08 (m, 2H), 2.01 - 1.94 (m, 1H), 1.87 (d, J = 13.5 Hz, 6H), 1.62 (d, J = 7.3 Hz, 5H), 1.33 (s, 12H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₇ClN₁₀O₇PS [M+H]⁺: 1111.5118, found, 1111.5111.

Compound Example 54: synthesis of N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin -2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)succinamide. (SIAIS164157)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS164119) was used to prepare SIAIS164157 (yellow solid, 11.0 mg, 61%). ¹H NMR (500 MHz, MeOD) δ 8.23 (s, 1H), 8.16 (s, 1H), 7.80 - 7.70 (m, 2H), 7.66 (t, J = 7.8 Hz, 1H), 7.55 (dd, J = 8.4, 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.38 (s, 1H), 7.14 - 7.10 (m, 2H), 7.04 (d, J = 7.1 Hz, 1H), 5.08 - 5.03 (m, 1H), 4.08 - 4.04 (m, 1H), 3.98 (s, 3H), 3.77 - 3.61 (m, 4H), 3.49 - 3.41 (m, 4H), 2.89 - 2.82 (m, 1H), 2.78 - 2.68 (m, 2H), 2.53 - 2.49 (m, 1H), 2.51 (s, 3H), 2.23 - 2.17 (m, 2H), 2.12 - 2.00 (m, 3H), 1.88 (s, 3H), 1.85 (s, 3H). HRMS (ESI) calcd for C₄₃H₄₉ClN₁₀O₈P⁺ [M+H]⁺: 899.3155, found, 899.0580.

Compound Example 55: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propenamide. (SIAIS219170)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue B and intermediate LM (SIAIS172147) was used to prepare SIAIS219170 (white solid, 6.4 mg, 39%). ¹H NMR (500 MHz, MeOD) δ 8.24 - 8.12 (m, 2H), 7.83 (d, J = 7.7 Hz, 1H), 7.78-7.71 (m, 4H), 7.65 (s, 1H), 7.47 (d, J = 6.7 Hz, 1H), 7.37-7.28 (m, 1H), 7.10-7.04 (m, 1H), 5.12 (dd, J = 12.5, 5.4 Hz, 1H), 4.04 (s, 1H), 3.97 (d, J = 4.3 Hz, 3H), 3.68-3.61 (m, 4H), 3.16 (t, J = 7.2 Hz, 2H), 2.91 - 2.82 (m, 1H), 2.78 - 2.66 (m, 2H), 2.63 (s, 2H), 2.16 - 2.06 (m, 3H), 1.87 (d, J = 13.5 Hz, 6H), 1.89-1.85 (m, 2H). HRMS (ESI) calcd for C₄₀H₄₃ClN₈O₇P⁺ [M+H]⁺: 813.2675, found, 813.2670.

Compound Example 56: synthesis of 4-((2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164007)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151001) was used to prepare SIAIS164007 (yellow solid, 17.5 mg, 71%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.72 - 7.65 (m, 1H), 7.61 - 7.54 (m, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 5.10 (dd, J = 12.7, 5.5 Hz, 1H), 3.86 (s, 3H), 3.84-3.75 (m, 6H), 3.53-3.51 (m, 4H), 3.43 - 3.32 (m, 2H), 3.30 - 2.95 (m, 5H), 2.90-2.83 (m, 2H), 2.81 - 2.54 (m, 5H), 2.21 - 2.01 (m, 3H), 1.89 (d, J = 13.6 Hz, 6H), 1.83 - 1.63 (m, 2H). HRMS (ESI) calcd for C₄₆H₅₅ClN₁₀O₈P [M+H]⁺: 941.3625, found, 941.2930.

Compound Example 57: synthesis of 4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy) ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164008)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151004) was used to prepare SIAIS164008 (yellow solid, 18.4 mg, 71%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.68 (dd, J = 14.7, 7.1 Hz, 1H), 7.60-7.54 (m, 2H), 7.37 (t, J = 7.0 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.52 (d, J = 8.2 Hz, 1H), 5.07 (dd, J = 12.5, 5.5 Hz, 1H), 3.89 (s, 1H), 3.87 (s, 1H), 3.84 (s, 3H), 3.78 (t, J = 5.8 Hz, 2H), 3.73 (t, J = 5.1 Hz, 2H), 3.69-3.68 (m, 2H), 3.67 - 3.63 (m, 2H), 3.51 (t, J = 5.1 Hz, 3H), 3.38-3.31 (m, 8H), 2.91 - 2.63 (m, 7H), 2.18 (d, J = 10.2 Hz, 2H), 2.15 - 2.05 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.86 - 1.73 (m, 2H). HRMS (ESI) calcd for C₄₈H₅₉ClN₁₀O₉P [M+H]⁺: 985.3887, found, 985.3166.

Compound Example 58: synthesis of 4-((2-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164009)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151005) was used to prepare SIAIS164009 (yellow solid, 20 mg, 74%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.07 (d, J = 14.7 Hz, 1H), 7.67 (dd, J = 14.7, 7.1 Hz, 1H), 7.61 - 7.51 (m, 2H), 7.37 (t, J = 7.1 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.08 (t, J = 6.2 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.53 (d, J = 9.0 Hz, 1H), 5.05 (dd, J = 12.5, 5.5 Hz, 1H), 3.91 (d, J = 12.4 Hz, 2H), 3.84 (s, 3H), 3.80 - 3.70 (m, 5H), 3.70 - 3.63 (m, 7H), 3.63 - 3.57 (m, 3H), 3.51-3.49 (m, 3H), 3.46 - 3.35 (m, 2H), 3.32-3.31 (m, 3H), 2.92 - 2.77 (m, 4H), 2.77 - 2.62 (m, 3H), 2.22 (d, J = 12.1 Hz, 2H), 2.12-2.08 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.86 - 1.79 (m, 2H). HRMS (ESI) calcd for C₅₀H₆₃ClN₁₀O₁₀P [M+H]⁺: 1029.4149, found, 1029.3401.

Compound Example 59: synthesis of 4-((15-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164016)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151006) was used to prepare SIAIS164016 (yellow solid, 13 mg, 46%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.68 (dd, J = 13.3, 8.4 Hz, 1H), 7.60-7..51 (m, 2H), 7.37 (t, J = 7.1 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 70 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 5.04 (dd, J = 12.7, 5.5 Hz, 1H), 3.93 (d, J = 12.7 Hz, 2H), 3.84 (s, 3H), 3.75 (t, J = 5.8 Hz, 3H), 3.71 (t, J = 5.2 Hz, 2H), 3.69 - 3.55 (m, 15H), 3.54 - 3.36 (m, 5H), 2.86-2.80 (m, 4H), 2.77 - 2.63 (m, 3H), 2.25 (d, J = 11.3 Hz, 2H), 2.15 - 2.04 (m, 1H), 1.90-1.86 (m, 8H). HRMS (ESI) calcd for C₅₂H₆₇ClN₁₀O₁₁P [M+H]⁺: 1073.4411, found, 1073.4778.

Compound Example 60: synthesis of 4-((18-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164017)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151007) was used to prepare SIAIS164017 (yellow solid, 18.2 mg, 62%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.05 (s, 1H), 7.67 (dd, J = 14.2, 6.5 Hz, 1H), 7.60-7.52 (m, 2H), 7.37 (t, J= 6.9 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 5.04 (dd, J = 12.6, 5.5 Hz, 1H), 3.95 (d, J = 12.2 Hz, 2H), 3.85 (s, 3H), 3.75 (dd, J = 12.5, 6.6 Hz, 2H), 3.71 (t, J = 5.2 Hz, 2H), 3.68 - 3.56 (m, 18H), 3.56 - 3.37 (m, 5H), 3.32-3.31 (m, 4H), 2.93 - 2.78 (m, 4H), 2.78 - 2.60 (m, 3H), 2.25 (d, J = 10.6 Hz, 2H), 2.11-2.07 (m, 1H), 1.90-1.87 (m, 8H). HRMS (ESI) calcd for C₅₄H₇₁ClN₁₀O₁₂P [M+H]⁺: 1117.4674, found, 1117.4682.

Compound Example 61: synthesis of 4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164018)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151025) was used to prepare SIAIS164018 (yellow solid, 18.1 mg, 78%). ¹H NMR (500 MHz, MeOD) δ 8.39 (s, 1H), 8.07 (d, J = 17.8 Hz, 1H), 7.68 (dd, J = 14.1, 7.7 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 7.0 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H), 5.09 (dd, J = 12.5, 5.5 Hz, 1H), 4.26 (s, 2H), 3.97 (d, J = 12.4 Hz, 2H), 3.86 (s, 3H), 3.71 - 3.32 (m, 9H), 2.98 - 2.81 (m, 3H), 2.79 - 2.68 (m, 2H), 2.27 (d, J = 11.4 Hz, 2H), 2.17 - 2.08 (m, 1H), 2.00 - 1.91 (m, 2H), 1.88 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₃H₄₉ClN₁₀O₇P [M+H]⁺: 883.3206, found, 883.3327.

Compound Example 62: synthesis of 4-((3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164019)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151026) was used to prepare SIAIS164019 (yellow solid, 14.2 mg, 60%). ¹H NMR (500 MHz, MeOD) δ 8.39 (s, 1H), 8.06 (s, 1H), 7.68 (dd, J = 13.4, 8.4 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.38 (t, J = 6.8 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 7.0 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 5.05 (dd, J= 12.5, 5.4 Hz, 1H), 3.93 (s, 2H), 3.86 (s, 3H), 3.72 (t, J = 5.2 Hz, 2H), 3.40 (t, J = 12.2 Hz, 2H), 3.32-3.31 (m, 6H), 2.86-2.79 (m, 5H), 2.77 - 2.64 (m, 3H), 2.17 (d, J = 12.1 Hz, 2H), 2.14 - 2.06 (m, 1H), 1.90-1.83 (m, 8H). HRMS (ESI) calcd for C₄₄H₅₁ClN₁₀O₇P [M+H]⁺: 897.3363, found, 897.3679.

Compound Example 63: synthesis of 4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164020)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151019) was used to prepare SIAIS164020 (yellow solid, 14.2 mg, 59%). ¹H NMR (500 MHz, MeOD) δ 8.40 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J = 13.4, 8.5 Hz, 1H), 7.60-7.57 (m, 2H), 7.39 (t, J = 70 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 6.9 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 8.5 Hz, 1H), 5.07 (dd, J = 12.6, 5.5 Hz, 1H), 3.94 (d, J = 12.4 Hz, 2H), 3.86 (s, 3H), 3.59 - 3.37 (m, 5H), 3.33-3.31 (m, 6H), 2.89 - 2.80 (m, 3H), 2.79 - 2.68 (m, 2H), 2.58 (s, 2H), 2.19 (s, 2H), 2.13-2.11 (m, 1H), 2.08 - 1.97 (m, 2H), 1.97 - 1.80 (m, 8H). HRMS (ESI) calcd for C₄₅H₅₃ClN₁₀O₇P [M+H]⁺: 911.3519, found, 911.3859.

Compound Example 64: synthesis of 4-((5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164021)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151020) was used to prepare SIAIS164021 (yellow solid, 20.6 mg, 85%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.07 (s, 1H), 7.69 (dd, J = 13.9, 7.5 Hz, 1H), 7.61-7.56 (m, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.34 (s, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 7.1 Hz, 1H), 6.78 (s, 1H), 6.63 (s, 1H), 5.07 (dd, J = 12.7, 5.5 Hz, 1H), 3.95 (s, 2H), 3.86 (s, 3H), 3.66 (m, 3H), 3.52 - 3.37 (m, 5H), 2.97 - 2.80 (m, 4H), 2.80 - 2.66 (m, 2H), 2.54 (s, 2H), 2.36 (t, J = 8.1 Hz, 1H), 2.27 (s, 2H), 2.17 - 2.08 (m, 1H), 2.04 (dt, J = 14.8, 7.5 Hz, 1H), 1.94 (s, 2H), 1.89 (d, J = 13.6 Hz, 6H), 1.75 (s, 4H). HRMS (ESI) calcd for C₄₆H₅₅ClN₁₀O₇P [M+H]⁺: 925.3676, found, 925.4004.

Compound Example 65: synthesis of 4-((6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164022)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151027) was used to prepare SIAIS164022 (yellow solid, 15.5 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.07 (d, J = 17.1 Hz, 1H), 7.68 (dd, J = 13.4, 7.1 Hz, 1H), 7.60-7.55 (m, 2H), 7.38 (t, J = 7.1 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 9.2, 7.9 Hz, 2H), 6.74 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 5.06 (dd, J = 12.5, 5.5 Hz, 1H), 3.95 (d, J = 11.7 Hz, 2H), 3.86 (s, 3H), 3.77 - 3.39 (m, 4H), 3.37 (t, J = 6.8 Hz, 2H), 3.35 - 3.31 (m, 5H), 2.91 - 2.80 (m, 3H), 2.80 - 2.64 (m, 2H), 2.49 (t, J = 7.3 Hz, 2H), 2.24 (d, J = 12.1 Hz, 2H), 2.19 - 2.04 (m, 1H), 1.90-1.87 (m, 8H), 1.78 - 1.65 (m, 4H), 1.57 - 1.43 (m, 2H). HRMS (ESI) calcd for C₄₇H₅₇ClN₁₀O₇P [M+H]⁺: 939.3832, found, 939.4168.

Compound Example 66: synthesis of 4-((7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS164023)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151086) was used to prepare SIAIS164023 (yellow solid, 14.1 mg, 56%). ¹H NMR (500 MHz, MeOD) δ 8.39 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J = 12.8, 7.8 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 2H), 7.38 (t, J = 7.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.05 (t, J = 7.8 Hz, 2H), 6.74 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 5.06 (dd, J = 12.5, 5.5 Hz, 1H), 3.96 (d, J = 12.7 Hz, 2H), 3.87 (s, 3H), 3.71-3.46 (m, 4H), 3.40 - 3.31 (m, 7H), 2.93 - 2.80 (m, 3H), 2.80 - 2.65 (m, 2H), 2.45 (t, J = 7.5 Hz, 2H), 2.25 (d, J = 11.5 Hz, 2H), 2.15 - 2.06 (m, 1H), 1.90-1.87 (m, 8H), 1.71-1.62 (m, 4H), 1.58 - 1.39 (m, 4H). HRMS (ESI) calcd for C₄₈H₅₉ClN₁₀O₇P [M+H]⁺: 953.3989, found, 953.4144.

Compound Example 67: synthesis of 3-(4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoi soindolin-2-yl)piperidine-2,6-dione. (SIAIS219073)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS 1204057) was used to prepare SIAIS219073 (yellow solid, 5.8 mg, 38%). ¹H NMR (500 MHz, MeOD) δ 8.33 (s, 1H), 8.11 (s, 1H), 7.74 - 7.68 (m, 1H), 7.60 (s, 1H), 7.45-7.36 (m, 3H), 7.18 (d, J = 7.5 Hz, 1H), 6.99 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 7.0 Hz, 1H), 5.19 - 5.15 (m, 1H), 4.44 (d, J = 16.8 Hz, 1H), 4.37 (d, J = 16.8 Hz, 1H), 4.25 (s, 1H), 3.96 (d, J = 12.7 Hz, 2H), 3.90 (s, 3H), 3.64-3.61 (m, 4H), 3.39-3.36 (m, 2H), 3.28 - 3.05 (m, 6H), 2.97 - 2.87 (m, 1H), 2.81 (d, J = 2.5 Hz, 1H), 2.54-2.50 (m, 1H), 2.37 (d, J = 11.1 Hz, 2H), 2.24 - 2.07 (m, 3H), 1.88 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₃H₅₁ClN₁₀O₆P⁺ [M+H]⁺: 869.3414, found, 869.3410.

Compound Example 68: synthesis of 3-(4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (SIAIS219155)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS1204085) was used to prepare SIAIS219155 (yellow solid, 7.0 mg, 45%). ¹H NMR (500 MHz, MeOD) δ 8.33 (s, 1H), 8.09 (s, 1H), 7.70 (dd, J = 14.0, 7.8 Hz, 1H), 7.60 (s, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.38 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.92 (s, 1H), 6.74 (s, 1H), 5.17 (dd, J = 13.2, 5.0 Hz, 1H), 4.43 (d, J = 17.3 Hz, 1H), 4.34 (d, J = 17.4 Hz, 1H), 3.97 - 3.87 (m, 4H), 3.77 - 3.47 (m, 2H), 3.46 - 3.31 (m, 8H), 3.17-3.05 (m, 4H), 2.97 - 2.89 (m, 1H), 2.85 - 2.78 (m, 1H), 2.58-2.49 (m, 3H), 2.32 - 2.17 (m, 3H), 2.09 - 1.92 (m, 4H), 1.88 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₅H₅₅ClN₁₀O₆P⁺ [M+H]⁺: 897.3727, found, 897.3722.

Compound Example 69: synthesis of 3-(4-((5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (SIAIS219156)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS1210133) was used to prepare SIAIS219156 (yellow solid, 7.5 mg, 47%). ¹H NMR (500 MHz, MeOD) δ 8.30 (s, 1H), 8.12 (s, 1H), 7.71 (dd, J = 13.4, 7.1 Hz, 1H), 7.61 (t, J = 70 Hz, 1H), 7.47 (dt, J = 12.9, 7.1 Hz, 3H), 7.37 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 7.04 (s, 1H), 6.84 (d, J = 8.7 Hz, 1H), 5.18 (dd, J = 13.3, 5.2 Hz, 1H), 4.50 (d, J = 17.1 Hz, 1H), 4.43 (d, J = 17.1 Hz, 1H), 3.95 (s, 1H), 3.91 (s, 3H), 3.77 - 3.47 (m, 4H), 3.38 (d, J = 3.4 Hz, 2H), 3.30-3.22 (m, 8H), 2.97 - 2.88 (m, 1H), 2.84 - 2.78 (m, 1H), 2.56-2.49 (m, 3H), 2.36 (s, 2H), 2.26 - 2.18 (m, 1H), 2.12-2.10 (m, 2H), 1.88 (d, J = 13.6 Hz, 6H), 1.77 (s, 4H). HRMS (ESI) calcd for C₄₆H₅₇ClN₁₀O₆P⁺ [M+H]⁺: 911.3883, found, 911.3878.

Compound Example 70: synthesis of 3-(4-((6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (SIAIS219157)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS 1204061) was used to prepare SIAIS219157 (yellow solid, 8.1 mg, 53%). ¹H NMR (500 MHz, MeOD) δ 8.28 (s, 1H), 8.13 (s, 1H), 7.71 (dd, J = 14.0, 7.7 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 6.5 Hz, 3H), 7.25 (d, J = 7.9 Hz, 1H), 7.08 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.54 (d, J = 17.1 Hz, 1H), 4.47 (d, J = 17.1 Hz, 1H), 3.95 (s, 1H), 3.91 (s, 3H), 3.67-3.57 (m, 4H), 3.38 (t, J = 7.1 Hz, 2H), 3.30-3.17 (m, 8H), 2.99 - 2.88 (m, 1H), 2.85 - 2.77 (m, 1H), 2.59 - 2.44 (m, 3H), 2.39 (d, J = 10.6 Hz, 2H), 2.27 - 2.08 (m, 3H), 1.88 (d, J = 13.6 Hz, 6H), 1.78-1.74 (m, 2H), 1.73 - 1.65 (m, 2H), 1.56 - 1.47 (m, 2H). HRMS (ESI) calcd for C₄₇H₅₉ClN₁₀O₆P⁺ [M+H]⁺: 925.4040, found, 925.4031.

Compound Example 71: synthesis of 3-(4-((7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (SIAIS219124)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS 1204063) was used to prepare SIAIS219124 (yellow solid, 11.2 mg, 48%). ¹H NMR (500 MHz, MeOD) δ 8.38 (s, 1H), 8.08 (s, 1H), 7.70 (dd, J = 13.9, 7.9 Hz, 1H), 7.59 (s, 1H), 7.45 - 7.37 (m, 2H), 7.33 (s, 1H), 7.16 (d, J = 7.3 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 6.64 (d, J = 8.4 Hz, 1H), 5.17 (dd, J = 13.2, 5.0 Hz, 1H), 4.38 (d, J = 17.0 Hz, 1H), 4.31 (d, J = 16.9 Hz, 1H), 3.98 (d, J = 12.6 Hz, 2H), 3.89 (d, J = 14.3 Hz, 3H), 3.57 (s, 2H), 3.47 (s, 2H), 3.19 (s, 6H), 2.95-2.89 (m, 4H), 2.82 (d, J = 15.7 Hz, 2H), 2.54 - 2.41 (m, 3H), 2.34 - 2.18 (m, 4H), 1.97 - 1.86 (m, 6H), 1.71-1.64 (m, 4H), 1.48 (s, 4H). HRMS (ESI) calcd for C₄₈H₆₁ClN₁₀O₆P⁺ [M+H]⁺: 939.4196, found, 939.4188.

Compound Example 72: synthesis of (2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164041)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS 151010) was used to prepare SIAIS164041 (white solid, 18.2 mg, 61%). ¹H NMR (500 MHz, MeOD) δ 8.91 (s, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J = 14.1, 7.7 Hz, 1H), 7.60-7.55 (m, 1H), 7.46 - 7.37 (m, 5H), 7.30 (s, 1H), 6.72 (d, J = 2.5 Hz, 1H), 6.58 (d, J= 8.7 Hz, 1H), 4.72 (s, 1H), 4.60 - 4.49 (m, 3H), 4.48 - 4.23 (m, 5H), 4.14 - 4.00 (m, 3H), 3.95 (d, J = 12.2 Hz, 2H), 3.91 - 3.83 (m, 5H), 3.82-3.74 (m, 7H), 3.48-3.44 (m, 2H), 2.85 (t, J = 12.2 Hz, 2H), 2.46 (s, 3H), 2.29-2.23 (m, 3H), 2.14 - 2.05 (m, 1H), 1.90-1.87 (m, 9H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₆H₇₄ClN₁₁O₉PS [M+H]⁺: 1142.4812, found, 1142.4776.

Compound Example 73: synthesis of (2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164032)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS 151002) was used to prepare SIAIS164032 (white solid, 15.4 mg, 50%). ¹H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J = 14.0, 7.6 Hz, 1H), 7.62 - 7.51 (m, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.45 - 7.36 (m, 3H), 7.29 (d, J = 9.4 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 4.66 (s, 1H), 4.60-4.50 (m, 3H), 4.37 (d, J = 15.5 Hz, 1H), 3.97 (d, J = 13.1 Hz, 2H), 3.89 (d, J = 11.2 Hz, 1H), 3.85 (s, 3H), 3.84 - 3.80 (m, 1H), 3.80 - 3.67 (m, 5H), 3.66 - 3.51 (m, 6H), 3.51 - 3.36 (m, 2H), 3.30 (s, 5H), 2.91-2.85 (m, 2H), 2.78 - 2.61 (m, 2H), 2.61 - 2.42 (m, 5H), 2.28-2.21 (m, 3H), 2.11-2.04 (m, 1H), 1.93-1.87 (m, 7H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₈ClN₁₁O₉PS [M+H]⁺: 1170.5125, found, 1170.5152.

Compound Example 74: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164033)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151003) was used to prepare SIAIS164033 (white solid, 24.9 mg, 78%). ¹H NMR (500 MHz, MeOD) δ 8.98 (s, 1H), 8.40 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J = 14.0, 7.6 Hz, 1H), 7.62 - 7.52 (m, 1H), 7.51 - 7.46 (m, 2H), 7.45-7.42 (m, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.28 (s, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 8.7 Hz, 1H), 4.65 (s, 1H), 4.60 - 4.47 (m, 3H), 4.37 (d, J = 15.6 Hz, 1H), 3.98 (d, J = 12.7 Hz, 2H), 3.89 (d, J = 11.2 Hz, 1H), 3.85 (s, 3H), 3.83 - 3.69 (m, 6H), 3.66 - 3.57 (m, 9H), 3.52 - 3.41 (m, 2H), 3.32-3.31 (m, 5H), 2.92-2.86 (m, 2H), 2.65-2.63 (m, 2H), 2.62 - 2.53 (m, 1H), 2.53 - 2.43 (m, 4H), 2.33 - 2.18 (m, 3H), 2.10-2.05 (m, 1H), 1.94-1.87 (m, 8H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₀H₈₂ClN₁₁O₁₀PS [M+H]⁺: 1214.5387, found, 1214.5405.

Compound Example 75: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164034)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151008) was used to prepare SIAIS164034 (white solid, 23.8 mg, 72%). ¹H NMR (500 MHz, MeOD) δ 8.94 (d, J = 3.1 Hz, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J = 13.5, 8.4 Hz, 1H), 7.62 - 7.52 (m, 1H), 7.51 - 7.45 (m, 2H), 7.45-7.41 (m, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.29 (s, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H), 4.65 (s, 1H), 4.59-4.50 (m, 3H), 4.36 (d, J = 15.5 Hz, 1H), 3.98 (d, J = 12.7 Hz, 2H), 3.92 - 3.83 (m, 4H), 3.82-3.70 (m, 6H), 3.65 - 3.56 (m, 14H), 3.47-3.44 (m, 2H), 3.32 (s, 6H), 2.87 (t, J = 12.5 Hz, 2H), 2.67 - 2.54 (m, 2H), 2.51 - 2.43 (m, 4H), 2.32 - 2.18 (m, 3H), 2.10-2.04 (m, 1H), 1.93-1.87 (m, 7H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₂H₈₆ClN₁₁O₁₁PS [M+H]⁺: 1258.5650, found, 1258.5713.

Compound Example 76: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164035)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS151009) was used to prepare SIAIS164035 (white solid, 18.7 mg, 55%). ¹H NMR (500 MHz, MeOD) δ 8.94 (s, 1H), 8.52 - 8.25 (m, 1H), 8.05 (s, 1H), 7.68 (dd, J = 14.8, 7.1 Hz, 1H), 7.60-7.55 (m, 1H), 7.51 - 7.46 (m, 2H), 7.45-7.41 (m, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.28 (s, 1H), 6.74 (s, 1H), 6.61 (s, 1H), 4.65 (s, 1H), 4.59 - 4.49 (m, 3H), 4.36 (d, J = 15.5 Hz, 1H), 3.98 (d, J = 13.0 Hz, 2H), 3.92 - 3.83 (m, 4H), 3.82 - 3.67 (m, 7H), 3.62-3.61 (m, 20H), 3.49-3.44 (m, 2H), 3.34-3.31 (m, 2H), 2.87 (t, J = 12.5 Hz, 2H), 2.68 - 2.53 (m, 2H), 2.51 - 2.44 (m, 4H), 2.28-2.20 (m, 3H), 2.10-2.04 (m, 1H), 1.94-1.87 (m, 8H), 1.04 (s, 9H). HRMS (ESI) calcd for C₆₄H₉₀ClN₁₁O₁₂PS [M+H]⁺: 1302.5912, found, 1302.5944.

Compound Example 77: synthesis of (2S,4R)-1-((S)-2-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164120)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074011) was used to prepare SIAIS164120 (white solid, 9.1 mg, 48%). ¹H NMR (500 MHz, MeOD) δ 9.62 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 7.70 (dd, J = 14.0, 9.1 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 6.98 (s, 1H), 6.80 (s, 1H), 4.61 (s, 1H), 4.59-4.54 (m, 2H), 4.50 (s, 1H), 4.40 (d, J = 15.8 Hz, 1H), 4.34 - 4.22 (m, 1H), 3.97 (d, J = 11.9 Hz, 2H), 3.92 - 3.86 (m, 4H), 3.81 (dd, J = 11.0, 3.9 Hz, 1H), 3.67-3.60 (m, 5H), 3.17 (s, 4H), 2.84 - 2.57 (m, 5H), 2.56 (s, 3H), 2.37 (d, J = 10.3 Hz, 2H), 2.28 - 2.19 (m, 1H), 2.19 - 2.05 (m, 3H), 1.88 (d, J = 13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₄H₇₀ClN₁₁O₇PS [M+H]⁺: 1082.4601, found, 1082.1363.

Compound Example 78: synthesis of (2S,4R)-1-((S)-2-(5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164121)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074012) was used to prepare SIAIS164121 (white solid, 6.3 mg, 33%). ¹H NMR (500 MHz, MeOD) δ 9.72 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.72 (dd, J = 13.9, 7.9 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.59 - 7.35 (m, 6H), 7.14 (s, 1H), 6.91 (s, 1H), 4.69 - 4.49 (m, 5H), 4.41 (d, J = 15.8 Hz, 1H), 4.31 - 4.16 (m, 1H), 3.95-3.92 (m, 6H), 3.81 (d, J = 7.8 Hz, 1H), 3.69 (s, 4H), 3.27 - 3.02 (m, 5H), 2.57 (s, 3H), 2.44-2.37 (m, 6H), 2.24-2.08 (m, 4H), 1.93-1.87 (m, 8H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₅H₇₂ClN₁₁O₇PS [M+H]⁺: 1096.4758, found, 1096.1472.

Compound Example 79: synthesis of (2S,4R)-1-((S)-2-(6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164122)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074013) was used to prepare SIAIS164122 (white solid, 8.6 mg, 44%). ¹H NMR (500 MHz, MeOD) δ 9.76 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.72 (dd, J = 13.9, 7.8 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.59 - 7.43 (m, 6H), 7.17 (s, 1H), 6.95 (s, 1H), 4.64 (s, 1H), 4.61 - 4.49 (m, 3H), 4.41 (d, J = 15.6 Hz, 1H), 4.25 (s, 1H), 3.99 - 3.88 (m, 6H), 3.81 (dd, J = 10.8, 3.8 Hz, 1H), 3.69 (s, 4H), 3.40-3.31 (m, 3H), 3.17 (s, 3H), 2.58 (s, 3H), 2.50-2.43 (m, 4H), 2.36-2.22 (m, 5H), 2.13 - 2.03 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.67 (s, 4H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₆H₇₄ClN₁₁O₇PS [M+H]⁺: 1110.4914, found, 1110.1540.

Compound Example 80: synthesis of (2S,4R)-1-((S)-2-(7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164123)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074014) was used to prepare SIAIS164123 (white solid, 8.4 mg, 43%). ¹H NMR (500 MHz, MeOD) δ 9.64 (s, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.71 (dd, J = 13.9, 7.7 Hz, 1H), 7.61 (s, 1H), 7.55-7.44 (m, 6H), 7.01 (s, 1H), 6.81 (s, 1H), 4.64 (s, 1H), 4.60-4.50 (m, 3H), 4.41 (d, J = 15.7 Hz, 1H), 3.96 (d, J = 10.3 Hz, 2H), 3.92-3.90 (m, 4H), 3.81 (dd, J = 10.9, 3.9 Hz, 1H), 3.69-3.60 (m, 4H), 3.31-3.17 (m, 7H), 2.56 (s, 3H), 2.47 (t, J = 7.3 Hz, 2H), 2.37 (s, 2H), 2.35 - 2.27 (m, 2H), 2.27 - 2.20 (m, 1H), 2.19 - 2.03 (m, 3H), 1.88 (d, J = 13.6 Hz, 6H), 1.70 - 1.59 (m, 4H), 1.43-1.37 (m, 2H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₆ClN₁₁O₇PS [M+H]⁺: 1124.5071, found, 1124.1726.

Compound Example 81: synthesis of (2S,4R)-1-((S)-2-(8-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164124)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074015) was used to prepare SIAIS164124 (white solid, 8.3 mg, 42%). ¹H NMR (500 MHz, MeOD) δ 9.76 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.72 (dd, J = 14.0, 7.9 Hz, 1H), 7.63 (s, 1H), 7.59 - 7.39 (m, 6H), 7.19 (s, 1H), 6.94 (s, 1H), 4.64 (s, 1H), 4.62 - 4.46 (m, 3H), 4.41 (d, J = 15.7 Hz, 1H), 4.26 (s, 1H), 4.03 - 3.86 (m, 6H), 3.81 (dd, J = 10.9, 3.8 Hz, 1H), 3.69 (s, 4H), 3.33 (s, 3H), 3.17 (s, 3H), 2.58 (s, 3H), 2.53 - 2.38 (m, 4H), 2.38 - 2.17 (m, 5H), 2.13 - 2.02 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.64 (d, J = 6.7 Hz, 4H), 1.39 (d, J = 3.5 Hz, 4H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₈ClN₁₁O₇PS [M+H]⁺: 1138.5227, found, 1138.1798.

Compound Example 82: synthesis of (2S,4R)-1-((S)-2-(9-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164125)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074016) was used to prepare SIAIS164125 (white solid, 8.9 mg, 44%). ¹H NMR (500 MHz, MeOD) δ 9.82 - 9.70 (m, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.78 - 7.68 (m, 1H), 7.64 (s, 1H), 7.56-7.47 (m, 6H), 7.23 (s, 1H), 6.98 (s, 1H), 4.64 (s, 1H), 4.61 - 4.47 (m, 3H), 4.40 (d, J = 15.7 Hz, 1H), 4.25 (s, 1H), 3.92 (t, J = 8.1 Hz, 6H), 3.81 (dd, J = 11.0, 3.8 Hz, 1H), 3.70 (s, 4H), 3.39-3.32 (m, 3H), 3.30-3.17 (m, 3H), 2.58 (s, 3H), 2.52 - 2.39 (m, 4H), 2.39 - 2.17 (m, 5H), 2.13 - 2.03 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.62 (s, 4H), 1.37 (s, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₉H₈₀ClN₁₁O₇PS [M+H]⁺: 1152.5384, found, 1152.1936.

Compound Example 83: synthesis of (2S,4R)-1-((S)-2-(10-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164126)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS074019) was used to prepare SIAIS164126 (white solid, 7.7 mg, 38%). ¹H NMR (500 MHz, MeOD) δ 9.88 - 9.79 (m, 1H), 8.19 (s, 2H), 7.73 (dd, J = 13.9, 7.8 Hz, 1H), 7.65 (s, 1H), 7.57-7.48 (m, 6H), 7.33 (s, 1H), 7.06 (s, 1H), 4.64 (s, 1H), 4.61 - 4.46 (m, 3H), 4.44 - 4.37 (m, 1H), 4.27 (s, 1H), 3.95-3.90 (m, 6H), 3.85 - 3.48 (m, 8H), 3.20-3.04 (m, 3H), 2.60 (s, 3H), 2.53 - 2.43 (m, 4H), 2.42 - 2.19 (m, 5H), 2.10-2.05 (m, 1H), 1.88 (d, J = 13.6 Hz, 6H), 1.62 (d, J = 7.0 Hz, 4H), 1.36 (s, 8H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₀H₈₂ClN₁₁O₇PS [M+H]⁺: 1166.5540, found, 1166.2102.

Compound Example 84: synthesis of 4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-4-oxobutanamide. (SIAIS164152)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS164119) was used to prepare SIAIS164152 (yellow solid, 10.6 mg, 63%). ¹H NMR (500 MHz, MeOD) δ 8.23 (s, 1H), 8.17 (s, 1H), 7.74 (dd, J = 13.8, 7.8 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.57 (dd, J = 8.5, 7.2 Hz, 1H), 7.50 (t, J = 7.3 Hz, 1H), 7.45 (s, 1H), 7.15 (t, J = 6.9 Hz, 2H), 7.06 (d, J = 7.1 Hz, 1H), 5.08 (dd, J = 12.7, 5.5 Hz, 1H), 4.72 (s, 1H), 4.27 (s, 1H), 3.97 (s, 3H), 3.93 (d, J = 12.2 Hz, 2H), 3.86 - 3.58 (m, 6H), 3.48 (s, 5H), 3.17 (s, 2H), 2.93-2.85 (m, 1H), 2.80 - 2.65 (m, 3H), 2.65 - 2.40 (m, 7H), 2.16 - 2.07 (m, 1H), 1.87 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₇H₅₆ClN₁₁O₈P [M+H]⁺: 968.3734, found, 968.1075.

Compound Example 85: synthesis of 4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS219158)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS172147) was used to prepare SIAIS219158 (white solid, 6.8 mg, 44%). ¹H NMR (500 MHz, MeOD) δ 8.31 (d, J = 12.2 Hz, 1H), 8.11 (s, 1H), 7.86 - 7.81 (m, 2H), 7.76 (dd, J = 7.8, 1.2 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.1 Hz, 2H), 6.99 (s, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.13 (dd, J = 12.6, 5.5 Hz, 1H), 3.94 (d, J = 12.8 Hz, 2H), 3.90 (s, 3H), 3.61-3.55 (m, 4H), 3.19-3.14 (m, 8H), 2.91-2.77 (m, 4H), 2.76-2.73 (m, 2H), 2.35 (d, J = 11.4 Hz, 2H), 2.18 - 2.06 (m, 3H), 1.91 - 1.87 (m, 6H). HRMS (ESI) calcd for C₄₄H₅₀ClN₉O₇P⁺ [M+H]⁺: 882.3254, found, 882.3242.

Compound Example 86: synthesis of (2S,4R)-1-((S)-2-(4-(4-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164153)

According to the procedures for the preparation of Compound Example 1, Brigatinib Analogue C and intermediate LM (SIAIS164128) was used to prepare SIAIS164153 (white solid, 9.2 mg, 44%). ¹H NMR (500 MHz, MeOD) δ 9.90 (s, 1H), 8.32 (s, 1H), 8.21 (s, 2H), 7.74 (dd, J = 13.7, 7.7 Hz, 1H), 7.69 - 7.58 (m, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.54 - 7.46 (m, 3H), 7.38 (s, 1H), 7.10 (s, 1H), 4.64 - 4.48 (m, 6H), 4.44-4.41 (m, 1H), 4.26 (s, 1H), 3.96-3.92 (m, 6H), 3.88 - 3.53 (m, 8H), 3.17 (s, 2H), 2.92 (s, 2H), 2.61-2.59 (m, 5H), 2.52 (s, 2H), 2.48 - 2.13 (m, 8H), 2.12 - 2.01 (m, 3H), 1.87 (d, J = 13.6 Hz, 6H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₀H₇₉ClN₁₄O₇PS [M+H]⁺: 1205.5398, found, 1205.1640.

Compound Example 87: synthesis of 8-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164011)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151001) was used to prepare SIAIS164011 (yellow solid, 16.6 mg, 47%). ¹H NMR (500 MHz, DMSO) δ 12.70 (s, 1H), 11.09 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.36 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.61 (t, J = 5.7 Hz, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 3.63 (t, J = 5.2 Hz, 6H), 3.48 (dd, J = 10.9, 5.4 Hz, 2H), 2.98 - 2.90 (m, 4H), 2.89-2.81 (m, 1H), 2.73 (q, J = 7.5 Hz, 2H), 2.65 (t, J = 6.6 Hz, 2H), 2.56-2.49 (m, 2H), 2.00-1.97 (m, 1H), 1.73 (s, 6H), 1.27 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₃H₄₄N₇O₇ [M+H]⁺: 770.3297, found, 770.2435.

Compound Example 88: synthesis of 8-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164012)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151004) was used to prepare SIAIS164012 (yellow solid, 28 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ 9.70 (s, 1H), 8.51-8.43 (m, 2H), 8.27 (s, 1H), 7.77 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.46-7.43 (m, 1H), 7.13 (s, 1H), 7.03-7.02 (m, 1H), 6.84 (dd, J = 8.6, 5.0 Hz, 1H), 6.43 (s, 1H), 4.96 (dd, J = 11.8, 5.4 Hz, 1H), 3.88-3.83 (m, 4H), 3.71-3.65 (m, 8H), 3.37 (s, 2H), 3.03 - 2.93 (m, 4H), 2.90-2.88 (m, 1H), 2.77-2.71 (m, 6H), 2.13 (s, 1H), 1.70 (dd, J = 7.3, 2.1 Hz, 6H), 1.34 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₅H₄₈N₇O₈ [M+H]⁺: 814.3559, found, 814.2643.

Compound Example 89: synthesis of 8-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164013)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151005) was used to prepare SIAIS164013 (yellow solid, 28.8 mg, 73%). ¹H NMR (500 MHz, CDCl₃) δ 10.76 (s, 1H), 9.09 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.27 (s, 1H), 7.75 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.41 (dd, J = 10.1, 5.5 Hz, 1H), 7.13 (s, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.42 (s, 1H), 5.03 - 4.87 (m, 1H), 3.83 (t, J = 6.2 Hz, 4H), 3.70 - 3.57 (m, 12H), 3.35 (s, 2H), 3.02 - 2.84 (m, 5H), 2.83 - 2.65 (m, 6H), 2.12 (s, 1H), 1.88-1.65 (m, 6H), 1.37 - 1.26 (m, 3H). HRMS (ESI) calcd for C₄₇H₅₂N₇O₉ [M+H]⁺: 858.3821, found, 858.2862.

Compound Example 90: synthesis of 8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164014)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151006) was used to prepare SIAIS164014 (yellow solid, 16.8 mg, 40%). ¹H NMR (500 MHz, CDCl₃) δ 10.04 (s, 1H), 8.62 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.54 (dd, J = 8.2, 1.3 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.14 (s, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.43 (s, 1 H), 4.94 (dd, J = 12.2, 5.4 Hz, 1H), 3.82 (t, J = 6.3 Hz, 4H), 3.73 - 3.57 (m, 16H), 3.38 (t, J = 5.1 Hz, 2H), 3.02 - 2.94 (m, 4H), 2.91-2.88 (m, 1H), 2.83 - 2.67 (m, 6H), 2.18 - 2.08 (m, 1H), 1.73 (d, J = 5.0 Hz, 6H), 1.33 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₉H₅₆N₇O₁₀ [M+H]⁺: 902.4083, found, 902.4401.

Compound Example 91: synthesis of 8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,121-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164015)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151007) was used to prepare SIAIS164015 (yellow solid, 17.8 mg, 41%). ¹H NMR (500 MHz, CDCl₃) δ 10.12 (s, 1H), 8.64 (s, 1H), 8.50 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H), 7.74 (d, J = 4.2 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.45 (dd, J = 12.4, 5.4 Hz, 1H), 7.17 (s, 1H), 7.09 - 7.02 (m, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.46 (s, 1H), 4.94 (dd, J = 12.0, 5.6 Hz, 1H), 3.83 (d, J = 3.2 Hz, 4H), 3.74 - 3.60 (m, 20H), 3.41 (d, J = 4.8 Hz, 2H), 2.98 (s, 4H), 2.91-2.88 (m, 1H), 2.81-2.69 (m, 6H), 2.15-2.13 (m, 1H), 1.74 - 1.71 (m, 6H), 1.34 (t, J = 7.4 Hz, 3H). HRMS (ESI) calcd for C₅₁H₆₀N₇O₁₁ [M+H]⁺: 946.4345, found, 946.4364.

Compound Example 92: synthesis of 8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,121-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164028)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151025) was used to prepare SIAIS164028 (yellow solid, 17.2 mg, 53%). ¹H NMR (500 MHz, DMSO) δ 12.71 (s, 1H), 11.11 (s, 1H), 8.32(d, J = 8.2 Hz, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.65-7.60 (m, 2H), 7.42 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.13 (s, 1H), 7.09 (d, J = 7.1 Hz, 1H), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 4.28 (d, J = 4.4 Hz, 2H), 3.74 (s, 2H), 3.70 (s, 2H), 3.05 (s, 2H), 3.01 (s, 2H), 3.05-2.87 (m, 1H), 2.78 (q, J = 7.5 Hz, 2H), 2.63 (s, 1H), 2.59-2.54 (m, 1H), 2.07-2.04 (m, 1H), 1.75 (s, 6H), 1.30 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₀H₃₈N₇O₆ [M+H]⁺: 712.2878, found, 712.2993.

Compound Example 93: synthesis of 8-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164029)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151026) was used to prepare SIAIS164029 (yellow solid, 16.8 mg, 50%). ¹H NMR (500 MHz, DMSO) δ 12.70 (s, 1H), 11.10 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.61 (t, J = 7.5 Hz, 2H), 7.38 (s, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.82 (t, J = 6.3 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 3.68 (s, 2H), 3.63 (s, 2H), 3.61 - 3.56 (m, 2H), 2.96-2.94 (m, 4H), 2.92 - 2.83 (m, 1H), 2.78 - 2.71 (m, 4H), 2.65 - 2.52 (m, 2H), 2.03-2.01 (m, 1H), 1.74 (s, 6H), 1.28 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₁H₄₀N₇O₆ [M+H]⁺: 726.3035, found, 726.3166.

Compound Example 94: synthesis of 8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164024)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151019) was used to prepare SIAIS164024 (yellow solid, 23.6 mg, 69%). ¹H NMR (500 MHz, CDCl₃) δ 9.09 (s, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.58 (dd, J = 8.2, 1.3 Hz, 1H), 7.51 (dd, J = 8.5, 7.2 Hz, 1H), 7.14 (s, 1H), 7.10 (d, J = 7.0 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.34 (s, 1H), 4.93 (dd, J = 12.4, 5.4 Hz, 1H), 3.85 (s, 2H), 3.66 (s, 2H), 3.43 (s, 2H), 2.99 (d, J = 4.5 Hz, 4H), 2.92-2.89 (m, 1H), 2.83 - 2.73 (m, 4H), 2.53 (t, J = 6.9 Hz, 2H), 2.18 - 2.11 (m, 1H), 2.10 - 2.03 (m, 2H), 1.76 (s, 6H), 1.35 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₂H₄₂N₇O₆ [M+H]⁺: 740.3191, found, 740.3471.

Compound Example 95: synthesis of 8-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164025)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151020) was used to prepare SIAIS164025 (yellow solid, 21 mg, 61%). ¹H NMR (500 MHz, CDCl₃) δ 9.49 (s, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.77 (d, J = 0.5 Hz, 1H), 7.56 (dd, J = 8.2, 1.3 Hz, 1H), 7.49 (dd, J = 8.5, 7.1 Hz, 1H), 7.16 (s, 1H), 7.09 (d, J = 6.9 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.25 (s, 1H), 4.90 (dd, J = 12.4, 5.4 Hz, 1H), 3.86 (s, 2H), 3.69 (s, 2H), 3.32 (t, J = 6.5 Hz, 2H), 3.07 - 2.95 (m, 4H), 2.89 (d, J = 13.2 Hz, 1H), 2.83 - 2.71 (m, 4H), 2.49 (t, J = 7.1 Hz, 2H), 2.16-2.12 (m, 1H), 1.86-1.82 (m, 2H), 1.78-1.75 (m, 8H), 1.35 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₃H₄₄N₇O₆ [M+H]⁺: 754.3348, found, 754.3630.

Compound Example 96: synthesis of 8-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164026)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151027) was used to prepare SIAIS164026 (yellow solid, 20.4 mg, 58%). ¹H NMR (500 MHz, CDCl₃) δ 9.22 (s, 1H), 8.54 (d, J = 8.2 Hz, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 7.58 (dd, J = 8.2, 1.3 Hz, 1H), 7.49 (dd, J = 8.5, 7.1 Hz, 1H), 7.16 (s, 1H), 7.09 (d, J = 6.9 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.23 (s, 1H), 4.92 (dd, J = 12.3, 5.4 Hz, 1H), 3.85 (s, 2H), 3.69 (s, 2H), 3.29 (t, J = 6.8 Hz, 2H), 3.04 - 2.97 (m, 4H), 2.912-2.89 (m, 1H), 2.82 - 2.73 (m, 4H), 2.45 (t, J = 7.5 Hz, 2H), 2.18 - 2.11 (m, 1H), 1.78 - 1.71 (m, 10H), 1.53-1.52 (m, 2H), 1.36 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₄H₄₆N₇O₆ [M+H]⁺: 768.3504, found, 768.3785.

Compound Example 97: synthesis of -(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS164030)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151086) was used to prepare SIAIS164030 (yellow solid, 19.4 mg, 54%). ¹H NMR (500 MHz, CDCl₃) δ 10.26 (s, 1H), 8.51 (d, J= 8.2 Hz, 1H), 8.30 (s, 2H), 7.76 (d, J = 0.5 Hz, 1H), 7.55 (dd, J = 8.2, 1.3 Hz, 1H), 7.47 (dd, J = 8.5, 7.1 Hz, 1H), 7.16 (s, 1H), 7.06 (t, J = 5.1 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.21 (s, 1H), 4.93 (dd, J = 12.2, 5.5 Hz, 1H), 3.88 (s, 2H), 3.72 (s, 2H), 3.25 (t, J = 7.0 Hz, 2H), 3.02 (dd, J = 9.9, 4.8 Hz, 4H), 2.91-2.88 (m, 1H), 2.85 - 2.70 (m, 4H), 2.46 (t, J = 7.5 Hz, 2H), 2.19 - 2.10 (m, 1H), 1.77 - 1.70 (m, 8H), 1.69 - 1.63 (m, 2H), 1.53 - 1.39 (m, 4H), 1.33 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₅H₄₈N₇O₆ [M+H]⁺: 782.3661, found, 782.3818.

Compound Example 98: synthesis of (2S,4R)-1-((S)-2-(2-(2-(2-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164040)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151010) was used to prepare SIAIS164040 (white solid, 29.7 mg, 66%). ¹H NMR (500 MHz, CDCl₃) δ 10.26 (s, 1H), 8.94 (s, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.29 (s, 1H), 7.78 (s, 1H), 7.56 (dd, J = 8.2, 1.3 Hz, 1H), 7.41 - 7.31 (m, 5H), 7.16 (s, 1H), 4.72 (t, J = 8.1 Hz, 1H), 4.61 - 4.51 (m, 3H), 4.36 (dd, J = 15.2, 5.4 Hz, 1H), 4.28 (s, 2H), 4.14 (d, J = 11.7 Hz, 1H), 4.11-4.00 (m, 2H), 3.85 - 3.58 (m, 9H), 3.46 - 3.39 (m, 2H), 3.00 (s, 4H), 2.88 (s, 3H), 2.76 (q, J = 7.6 Hz, 2H), 2.55 (s, 3H), 2.53-2.49 (m, 1H), 2.45 (t, J = 8.2 Hz, 2H), 2.09 - 2.00 (m, 3H), 1.73 (d, J = 3.4 Hz, 6H), 1.34 (t, J = 7.5 Hz, 3H), 0.97 (s, 9H). HRMS (ESI) calcd for C₅₃H₆₃N₈O₈S [M+H]⁺: 971.4484, found, 971.4483.

Compound Example 99: synthesis of (2S,4R)-1-((S)-2-(3-(2-(3-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihy dro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164036)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151002) was used to prepare SIAIS164036 (white solid, 16.1 mg, 35%). ¹H NMR (500 MHz, CDCl₃) δ 10.34 (s, 1H), 9.08 (s, 1H), 8.50 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.55 (dd, J = 8.2, 1.3 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.11 (s, 1H), 4.74 (t, J = 8.2 Hz, 1H), 4.66 (dd, J = 15.5, 6.8 Hz, 1H), 4.58 (s, 1H), 4.54 (d, J = 8.4 Hz, 1H), 4.34 (dd, J = 15.4, 5.2 Hz, 1H), 4.18 (d, J = 11.4 Hz, 1H), 3.85 - 3.72 (m, 5H), 3.71 - 3.58 (m, 8H), 2.96 - 2.95 (m, 4H), 2.77 - 2.72 (m, 2H), 2.70 (t, J = 6.3 Hz, 2H), 2.58 (s, 3H), 2.56 - 2.49 (m, 2H), 2.47 - 2.37 (m, 1H), 2.29 - 2.21 (m, 1H), 1.71 (d, J = 3.1 Hz, 6H), 1.32 (t, J = 7.5 Hz, 3H), 0.97 (s, 9H). HRMS (ESI) calcd for C₅₅H₆₇N₈O₈S [M+H]⁺: 999.4797, found, 999.4847.

Compound Example 100: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164037)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151003) was used to prepare SIAIS164037 (white solid, 34.6 mg, 72%). ¹H NMR (500 MHz, CDCl₃) δ 10.62 (s, 1H), 9.10 (s, 1H), 8.50 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H), 7.78 (s, 1H), 7.54 (dd, J = 8.2, 1.3 Hz, 1H), 7.46 (d, J = 6.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.14 (s, 1H), 4.73 (t, J = 8.3 Hz, 1H), 4.63 (dd, J = 15.3, 6.8 Hz, 1H), 4.57-4.54 (m, 2H), 4.34 (dd, J = 15.3, 5.1 Hz, 1H), 4.17 (d, J = 11.4 Hz, 1H), 3.81-3.75 (m, 5H), 3.72 - 3.59 (m, 12H), 2.99-2.96 (m, 4H), 2.80 - 2.67 (m, 4H), 2.56 (s, 3H), 2.56-2.54 (m, 2H), 2.44 - 2.34 (m, 1H), 2.29-2.24 (m, 1H), 1.72 (d, J = 2.7 Hz, 6H), 1.33 (t, J = 7.5 Hz, 3H), 0.99 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₁N₈O₉S [M+H]⁺: 1043.5059, found, 1043.5097.

Compound Example 101: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164038)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151008) was used to prepare SIAIS164038 (white solid, 32.5 mg, 65%). ¹H NMR (500 MHz, CDCl₃) δ 10.78 (s, 1H), 9.08 (s, 1H), 8.50 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H), 7.77 (s, 1H), 7.53 (dd, J = 8.2, 1.3 Hz, 1H), 7.39-7.37 (m, 3H), 7.34 (d, J = 8.2 Hz, 2H), 7.15 (s, 1H), 4.73 (t, J = 8.0 Hz, 1H), 4.65 - 4.56 (m, 2H), 4.54 (d, J = 8.3 Hz, 1H), 4.35 (dd, J = 15.3, 5.2 Hz, 1H), 4.14 (d, J = 11.4 Hz, 1H), 3.82-3.81 (m, 4H), 3.70-3.67 (m, 5H), 3.63-3.61 (m, 12H), 3.00-2.96 (m, 4H), 2.78-2.71 (m, 4H), 2.54 (s, 3H), 2.52 (s, 2H), 2.41-2.39 (m, 1H), 2.28-2.27 (m, 1H), 1.73 (s, 6H), 1.32 (t, J = 7.5 Hz, 3H), 0.98 (s, 9H). HRMS (ESI) calcd for C₅₉H₇₅N₈O₁₀S [M+H]⁺: 1087.5321, found, 1087.5342.

Compound Example 102: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164039)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS151009) was used to prepare SIAIS164039 (white solid, 40.1 mg, 77%). ¹H NMR (500 MHz, CDCl₃) δ 10.84 (s, 1H), 9.03 (s, 1H), 8.50 (d, J = 8.2 Hz, 1H), 8.29 (s, 1H), 7.78 (s, 1H), 7.54 (dd, J = 8.2, 1.3 Hz, 1H), 7.37 (q, J = 8.2 Hz, 5H), 7.22 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 4.74 (t, J = 7.8 Hz, 1H), 4.63-4.59 (m, 2H), 4.54 (d, J = 8.4 Hz, 1H), 4.36 (dd, J = 15.2, 5.1 Hz, 1H), 4.14 (d, J = 11.2 Hz, 1H), 3.83 (s, 4H), 3.75 - 3.68 (m, 4H), 3.65-3.61 (m, 16H), 3.01 (s, 2H), 2.97 (s, 2H), 2.79-2.76 (m, 2H), 2.75-2.71 (m, 3H), 2.54 (s, 3H), 2.53-2.52 (m, 2H), 2.44-2.43 (m, 1H), 2.26-2.25 (m, 1H), 1.75 (d, J = 4.9 Hz, 6H), 1.34 (t, J = 7.5 Hz, 3H), 0.98 (s, 9H). HRMS (ESI) calcd for C₆₁H₇₉N₈O₁₁S [M+H]⁺: 1131.5584, found, 1131.5582.

Compound Example 103: synthesis of (2S,4R)-1-((S)-2-(4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164093)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074011) was used to prepare SIAIS164093 (white solid, 21.2 mg, 67%). ¹H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 8.99 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.95 (d, J = 9.3 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.41 (q, J = 8.2 Hz, 5H), 4.55 (d, J = 9.4 Hz, 1H), 4.43 (dd, J = 14.3, 6.9 Hz, 2H), 4.36 (s, 1H), 4.22 (dd, J = 16.0, 5.5 Hz, 1H), 3.64 (s, 7H), 2.99 (s, 2H), 2.93 (s, 2H), 2.76 (q, J = 7.4 Hz, 2H), 2.65 - 2.54 (m, 3H), 2.45-2.42 (m, 4H), 2.09 - 1.99 (m, 1H), 1.96 - 1.86 (m, 1H), 1.74 (s, 6H), 1.29 (t, J = 7.5 Hz, 3H), 0.94 (s, 9H). HRMS (ESI) calcd for C₅₁H₅₉NaO₆S [M+H]⁺: 911.4273, found, 911.4539.

Compound Example 104: synthesis of (2S,4R)-1-((S)-2-(5-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164094)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074012) was used to prepare SIAIS164094 (white solid, 16.7 mg, 52%). ¹H NMR (500 MHz, DMSO) δ 12.73 (s, 1H), 8.97 (s, 1H), 8.56 (t, J = 5.9 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.92 (d, J = 9.5 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.45 - 7.35 (m, 5H), 4.56 (d, J = 9.3 Hz, 1H), 4.42 (dd, J = 16.5, 8.2 Hz, 2H), 4.35 (s, 1H), 4.21 (dd, J = 15.9, 5.4 Hz, 1H), 3.73 - 3.59 (m, 7H), 2.98 (s, 2H), 2.92 (s, 2H), 2.75 (q, J = 7.4 Hz, 2H), 2.43 (s, 3H), 2.36 (t, J = 7.4 Hz, 2H), 2.33 - 2.19 (m, 2H), 2.06-2.02 (m, 1H), 1.93-1.88 (m, 1H), 1.75-1.72 (m, 8H), 1.28 (t, J = 7.5 Hz, 3H), 0.94 (s, 9H). HRMS (ESI) calcd for C₅₂H₆₁N₈O₆S [M+H]⁺: 925.4429, found, 925.4685.

Compound Example 105: synthesis of (2S,4R)-1-((S)-2-(6-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164095)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074013) was used to prepare SIAIS164095 (white solid, 19.6 mg, 60%). ¹H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 8.98 (s, 1H), 8.56 (t, J = 5.8 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.44 - 7.36 (m, 5H), 4.56 (d, J = 9.5 Hz, 1H), 4.49 - 4.39 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J = 15.8, 5.4 Hz, 1H), 3.68 - 3.64 (m, 8H), 2.98 (s, 2H), 2.92 (s, 2H), 2.75 (q, J = 7.4 Hz, 2H), 2.44 (s, 3H), 2.37 (s, 2H), 2.34 - 2.28 (m, 1H), 2.20 - 2.12 (m, 1H), 2.07 - 2.00 (m, 1H), 1.94 - 1.87 (m, 1H), 1.75 (s, 6H), 1.53 (d, J = 6.8 Hz, 4H), 1.28 (t, J = 7.5 Hz, 3H), 0.94 (s, 9H). HRMS (ESI) calcd for C₅₃H₆₃N₈O₆S [M+H]⁺: 939.4586, found, 939.4864.

Compound Example 106: synthesis of (2S,4R)-1-((S)-2-(7-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164096)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074014) was used to prepare SIAIS164096 (white solid, 21.6 mg, 66%). ¹H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 8.98 (s, 1H), 8.56 (t, J = 5.9 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.86 (d, J = 9.3 Hz, 1H), 7.61 (dd, J = 8.1, 1.2 Hz, 1H), 7.44 - 7.36 (m, 5H), 4.55 (d, J = 9.4 Hz, 1H), 4.45-4.41 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J = 15.9, 5.5 Hz, 1H), 3.69 - 3.62 (m, 7H), 2.97 (s, 2H), 2.93 (s, 2H), 2.75 (q, J = 7.5 Hz, 2H), 2.44 (s, 3H), 2.37 - 2.32 (m, 2H), 2.31 - 2.24 (m, 1H), 2.18 - 2.11 (m, 1H), 2.06-2.00 (m, 1H), 1.94 - 1.87 (m, 1H), 1.75 (s, 6H), 1.55-1.49 (m, 4H), 1.32 - 1.25 (m, 5H), 0.93 (d, J= 11.4 Hz, 9H). HRMS (ESI) calcd for C₅₄H₆₅N₈O₆S [M+H]⁺: 953.4742, found, 953.4991.

Compound Example 107: synthesis of (2S,4R)-1-((S)-2-(8-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihy dro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164097)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074015) was used to prepare SIAIS164097 (white solid, 22.6 mg, 68%). ¹H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 8.99 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.45 - 7.36 (m, 5H), 4.55 (d, J = 9.4 Hz, 1H), 4.45-4.41 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J = 16.0, 5.3 Hz, 1H), 3.65-3.63 (m, 7H), 2.97 (s, 2H), 2.93 (s, 2H), 2.75 (q, J = 7.5 Hz, 2H), 2.44 (s, 3H), 2.38 - 2.33 (m, 2H), 2.30-2.24 (m, 1H), 2.16-2.10 (m, 1H), 2.06 - 1.99 (m, 1H), 1.94 - 1.86 (m, 1H), 1.75 (s, 6H), 1.52-1.47 (m, 4H), 1.30-1.27 (m, 7H), 0.93 (s, 9H). HRMS (ESI) calcd for C₅₅H₆₇N₈O₆S [M+H]⁺: 967.4899, found, 967.5164.

Compound Example 108: synthesis of (2S,4R)-1-((S)-2-(9-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164098)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074016) was used to prepare SIAIS164098 (white solid, 21.8 mg, 64%). ¹H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 8.99 (s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.84 (d, J = 9.3 Hz, 1H), 7.61 (dd, J = 8.1, 1.2 Hz, 1H), 7.44 - 7.36 (m, 5H), 4.55 (d, J = 9.4 Hz, 1H), 4.45-4.41 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J = 16.0, 5.6 Hz, 1H), 3.66-3.63 (m, 7H), 2.97 (s, 2H), 2.92 (s, 2H), 2.75 (q, J = 7.5 Hz, 2H), 2.44 (s, 3H), 2.35 (t, J = 7.5 Hz, 2H), 2.31 - 2.23 (m, 1H), 2.16 - 2.08 (m, 1H), 2.05 - 2.00 (m, 1H), 1.92-1.87 (m, 1H), 1.75 (s, 6H), 1.52-1.46 (m, 4H), 1.30-1.27 (m, 9H), 0.92 (s, 9H). HRMS (ESI) calcd for C₅₆H₆₉N₈O₆S [M+H]⁺: 981.5055, found, 981.5349.

Compound Example 109: synthesis of (2S,4R)-1-((S)-2-(10-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164099)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS074019) was used to prepare SIAIS164099 (white solid, 20.1 mg, 59%). ¹H NMR (500 MHz, DMSO) δ 12.77 (s, 1H), 8.99 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.84 (d, J = 9.4 Hz, 1H), 7.60 (dd, J = 8.1, 1.2 Hz, 1H), 7.42-7.37 (m, 5H), 4.54 (d, J = 9.4 Hz, 1H), 4.45-4.41 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J = 15.9, 5.4 Hz, 1H), 3.69 - 3.63 (m, 7H), 2.97 (s, 2H), 2.92 (s, 2H), 2.75 (q, J = 7.5 Hz, 2H), 2.44 (s, 3H), 2.35 (t, J = 7.4 Hz, 2H), 2.30 - 2.22 (m, 1H), 2.11 (dt, J = 14.4, 6.5 Hz, 1H), 2.06 - 1.99 (m, 1H), 1.93-1.87 (m, 1H), 1.75 (s, 6H), 1.53-1.46 (m, 4H), 1.30-1.27 (m, 11H), 0.92 (s, 9H). HRMS (ESI) calcd for C₅₇H₇₁N₈O₆S [M+H]⁺: 995.5212, found, 995.5518.

Compound Example 110: synthesis of 4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-4-oxobutanamide. (SIAIS164154)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS164119) was used to prepare SIAIS164154 (yellow solid, 9 mg, 49%). ¹H NMR (500 MHz, DMSO) δ 12.73 (s, 1H), 11.09 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.11 (t, J = 5.3 Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.60 (dd, J = 12.1, 5.6 Hz, 2H), 7.39 (s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.75 (s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.63 (s, 4H), 3.29 - 3.21 (m, 2H), 2.98 (s, 2H), 2.92 (s, 2H), 2.88-2.85 (m, 1H), 2.75 (q, J = 7.4 Hz, 2H), 2.66 - 2.51 (m, 6H), 2.35 (t, J = 7.0 Hz, 2H), 2.05 - 1.98 (m, 1H), 1.75 (s, 6H), 1.29 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₄H₄₅N₈O₇ [M+H]⁺: 797.3406, found, 797.1339.

Compound Example 111: synthesis of (2S,4R)-1-((S)-2-(4-(4-(4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS164155)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue A and intermediate LM (SIAIS164128) was used to prepare SIAIS164155 (white solid, 9 mg, 38%). ¹H NMR (500 MHz, DMSO) δ 12.82 (s, 1H), 9.01 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 7.99 (d, J = 10.0 Hz, 2H), 7.90 (s, 1H), 7.60 (dd, J = 8.1, 1.2 Hz, 1H), 7.46 - 7.34 (m, 6H), 4.53 (d, J = 9.3 Hz, 1H), 4.46 - 4.39 (m, 2H), 4.35 (s, 1H), 4.30 (t, J = 7.1 Hz, 2H), 4.21 (dd, J = 15.8, 5.4 Hz, 1H), 2.97 (s, 2H), 2.93 (s, 2H), 2.75 (q, J = 7.4 Hz, 2H), 2.69-2.64 (m, 3H), 2.49 - 2.34 (m, 7H), 2.29-2.23 (m, 1H), 2.21 - 2.13 (m, 1H), 2.11 - 1.94 (m, 4H), 1.94 - 1.79 (m, 4H), 1.75 (s, 7H), 1.28 (t, J = 7.5 Hz, 3H), 0.93 (s, 9H). HRMS (ESI) calcd for C₅₇H₆₈N₁₁O₆S [M+H]⁺: 1034.5069, found, 1034.2256.

Compound Example 112: synthesis of N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propenamide. (SIAIS219023)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS 151004) was used to prepare SIAIS219023 (yellow solid, 9.8 mg, 49%). ¹H NMR (500 MHz, MeOD) δ 8.41 (d, J = 8.1 Hz, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.60 - 7.51 (m, 3H), 7.08 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 5.06 (dd, J = 12.5, 5.5 Hz, 1H), 4.14 (d, J = 17.1 Hz, 1H), 3.96 (t, J = 11.3 Hz, 1H), 3.80-3.73 (m, 2H), 3.69 - 3.61 (m, 6H), 3.50 (t, J = 5.2 Hz, 2H), 3.20 (d, J = 27.6 Hz, 4H), 2.89 - 2.69 (m, 6H), 2.48 (t, J = 6.1 Hz, 2H), 2.10 (d, J = 4.6 Hz, 2H), 1.88 - 1.75 (m, 8H), 1.37-1.29 (m, 2H). HRMS (ESI) calcd for C₄₆H₅₀N₇O₈ [M+H]⁺: 828.3715, found, 828.3762.

Compound Example 113: synthesis of N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-amide. (SIAIS219024)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS151006) was used to prepare SIAIS219024 (yellow solid, 11.2 mg, 51%). ¹H NMR (500 MHz, MeOD) δ 8.41 (d, J = 8.1 Hz, 1H), 8.33 (s, 1H), 7.88 (s, 2H), 7.58 (dd, J = 8.2, 1.4 Hz, 1H), 7.50 (dd, J = 8.5, 7.1 Hz, 1H), 7.02 (dd, J = 14.9, 7.8 Hz, 2H), 5.06 (dd, J = 12.6, 5.5 Hz, 1H), 4.10 (t, J = 10.9 Hz, 1H), 3.76 (t, J = 6.1 Hz, 2H), 3.69 - 3.54 (m, 14H), 3.47 - 3.41 (m, 2H), 3.17 (s, 4H), 2.94 - 2.83 (m, 3H), 2.77 - 2.67 (m, 2H), 2.49 (t, J = 6.0 Hz, 2H), 2.24 (d, J = 11.8 Hz, 2H), 2.14 - 2.00 (m, 3H), 1.83 (s, 4H), 1.42 (t, J = 7.5 Hz, 3H), 1.35 - 1.24 (m, 2H). HRMS (ESI) calcd for C₅₀H₅₈N₇O₁₀ [M+H]⁺: 916.4240, found, 916.4319.

Compound Example 114: synthesis of N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide. (SIAIS219001)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS151025) was used to prepare SIAIS219001 (yellow solid, 7.4 mg, 42%). ¹H NMR (500 MHz, DMSO) δ 12.71 (s, 1H), 11.11 (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.63-7.59 (m, 2H), 7.37 (s, 1H), 7.08 (d, J = 6.7 Hz, 1H), 6.97-6.93 (m, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 3.97 (s, 4H), 3.82 (s, 2H), 2.86-2.84 (m, 3H), 2.70 (d, J = 7.4 Hz, 4H), 1.90 (s, 2H), 1.75 (s, 6H), 1.66 (s, 2H), 1.27 (t, J = 7.4 Hz, 3H). HRMS (ESI) calcd for C₄₁H₄₀N₇O₆ [M+H]⁺: 726.3035, found, 726.3045.

Compound Example 115: synthesis of N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanamide. (SIAIS219010)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS151019) was used to prepare SIAIS219010 (yellow solid, 7.2 mg, 40%). ¹H NMR (500 MHz, DMSO) δ 12.70 (s, 1H), 11.10 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.36 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.64 (t, J = 6.1 Hz, 1H), 5.06 (dd, J = 12.7, 5.4 Hz, 1H), 3.77 (s, 1H), 3.15 (d, J = 12.3 Hz, 2H), 2.88-2.83 (m, 3H), 2.69 (q, J = 7.4 Hz, 2H), 2.63-2.58 (m, 2H), 2.19 (t, J = 7.2 Hz, 2H), 2.05 - 2.00 (m, 1H), 1.89 (d, J = 10.3 Hz, 2H), 1.85 - 1.79 (m, 2H), 1.75 (s, 6H), 1.62 - 1.53 (m, 2H), 1.28-1.24 (m, 5H). HRMS (ESI) calcd for C₄₃H₄₄N₇O₆ [M+H]⁺: 754.3348, found, 754.3170.

Compound Example 116: synthesis of N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide. (SIAIS219011)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS151027) was used to prepare SIAIS219011 (yellow solid, 8.8 mg, 47%). ¹H NMR (500 MHz, DMSO) δ 12.72 (s, 1H), 11.13 (s, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.37 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 6.65 (t, J = 6.1 Hz, 1H), 5.08 (dd, J = 12.7, 5.4 Hz, 1H), 3.78 (s, 1H), 3.17 (d, J = 12.3 Hz, 2H), 2.88-2.85 (m, 3H), 2.70 (q, J = 7.4 Hz, 2H), 2.61-2.59 (m, 2H), 2.21 (t, J = 7.2 Hz, 2H), 2.06 - 2.01 (m, 4H), 1.90 (d, J = 10.3 Hz, 2H), 1.86 - 1.79 (m, 2H), 1.77 (s, 6H), 1.62 - 1.54 (m, 2H), 1.29-1.27 (m, 6H). HRMS (ESI) calcd for C₄₅H₄₈N₇O₆ [M+H]⁺: 782.3661, found, 782.3465.

Compound Example 117: synthesis of N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)adipamide. (SIAIS219020)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS074013) was used to prepare SIAIS219020 (white solid, 9.9 mg, 43%). ¹H NMR (500 MHz, MeOD) δ 9.81 (s, 1H), 8.43 - 8.39 (m, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.88 (s, 1H), 7.58-7.49 (m, 5H), 4.64 (s, 1H), 4.60 - 4.49 (m, 3H), 4.41 (d, J = 15.7 Hz, 1H), 4.08 (s, 1H), 3.92 (d, J = 11.1 Hz, 1H), 3.81 (dd, J = 11.0, 3.9 Hz, 1H), 3.61 (d, J = 9.8 Hz, 2H), 3.54 (s, 2H), 2.94-2.86 (m, 2H), 2.58 (s, 3H), 2.39 - 2.19 (m, 8H), 2.08-2.05 (m, 2H), 1.85 (s, 6H), 1.67-1.66 (m, 4H), 1.41 (t, J = 7.5 Hz, 3H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₄H₆₅N₈O₆S [M+H]⁺: 953.4742, found, 953.4074.

Compound Example 118: synthesis of N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamide. (SIAIS219021)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue B and intermediate LM (SIAIS074019) was used to prepare SIAIS219021 (white solid, 11.2 mg, 46%). ¹H NMR (500 MHz, MeOD) δ 9.60 (s, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.26 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.57 - 7.47 (m, 5H), 4.64 (s, 1H), 4.59 - 4.52 (m, 2H), 4.50 (s, 1H), 4.39 (d, J = 15.7 Hz, 1H), 3.98 (s, 1H), 3.91 (d, J = 11.1 Hz, 1H), 3.80 (dd, J = 11.0, 3.9 Hz, 1H), 3.45-3.44 (m, 2H), 3.29 - 3.22 (m, 2H), 2.86 (q, J = 7.4 Hz, 2H), 2.55 (d, J = 2.9 Hz, 3H), 2.29-2.21 (m, 5H), 2.14 - 2.06 (m, 3H), 1.89 (d, J = 10.8 Hz, 2H), 1.83 (s, 6H), 1.63 (d, J = 6.4 Hz, 4H), 1.39 - 1.34 (m, 12H), 1.04 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₃N₈O₆S [M+H]⁺: 1009.5368, found, 1009.4649.

Compound Example 119: synthesis of 8-(4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS219018)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS151004) was used to prepare SIAIS219018 (yellow solid, 8.8 mg, 47%). ¹H NMR (500 MHz, DMSO) δ 12.81 (s, 1H), 11.10 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 3.0 Hz, 1H), 8.01 (s, 1H), 7.62-7.58 (m, 2H), 7.35 (s, 1H), 7.16 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 6.9 Hz, 1H), 6.61 (s, 1H), 5.06 (dd, J = 12.7, 5.4 Hz, 1H), 4.51 (d, J = 11.5 Hz, 1H), 4.11 (d, J = 15.1 Hz, 1H), 3.67 - 3.46 (m, 14H), 3.33 - 3.24 (m, 6H), 3.12 - 3.05 (m, 1H), 2.92 - 2.78 (m, 3H), 2.73-2.68 (m, 2H), 2.66 - 2.53 (m, 3H), 2.25 - 2.16 (m, 2H), 2.06 - 1.99 (m, 1H), 1.96 - 1.85 (m, 2H), 1.76 (d, J = 2.0 Hz, 6H), 1.30-1.26 (m, 3H). HRMS (ESI) calcd for C₅₀H₅₇N₈O₈ [M+H]⁺: 897.4294, found, 897.3670.

Compound Example 120: synthesis of 8-(4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS219019)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS151006) was used to prepare SIAIS219019 (yellow solid, 10.1 mg, 49%). ¹H NMR (500 MHz, DMSO) δ 12.84 (s, 1H), 11.09 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 30 Hz, 1H), 8.00 (s, 1H), 7.61 - 7.56 (m, 2H), 7.36 (s, 1H), 7.15 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.60 (s, 1H), 5.05 (dd, J = 12.8, 5.5 Hz, 1H), 4.51 (d, J = 13.5 Hz, 1H), 4.12 (d, J = 13.9 Hz, 1H), 3.66 - 3.60 (m, 4H), 3.60 - 3.46 (m, 20H), 3.30 (s, 4H), 3.12 (t, J = 12.9 Hz, 2H), 2.91 - 2.78 (m, 3H), 2.73-2.68 (m, 3H), 2.26 - 2.19 (m, 2H), 2.3-2.002 (m, 1H), 1.95 - 1.87 (m, 2H), 1.76 (s, 6H), 1.30-1.26 (m, 3H). HRMS (ESI) calcd for C₅₄H₆₅N₈O₁₀ [M+H]⁺: 985.4818, found, 985.4897.

Compound Example 121: synthesis of 8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS184194)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS151025) was used to prepare SIAIS184194 (yellow solid, 6.2 mg, 37%). ¹H NMR (500 MHz, DMSO) δ 12.78 (s, 1H), 11.11 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.65 - 7.59 (m, 2H), 7.37 (s, 1H), 7.12 (dd, J = 14.8, 7.8 Hz, 2H), 7.04 (s, 1H), 5.08 (dd, J = 12.5, 5.4 Hz, 1H), 4.58 - 4.52 (m, 1H), 4.28 - 4.21 (m, 1H), 3.61 (s, 2H), 3.48 (d, J = 5.2 Hz, 3H), 3.44 - 3.40 (m, 8H), 2.83 (s, 3H), 2.72 (d, J = 7.5 Hz, 2H), 2.28 - 2.18 (m, 2H), 2.08 - 2.01 (m, 1H), 1.95 - 1.88 (m, 2H), 1.76 (s, 6H), 1.29 (t, J = 7.5 Hz, 3H). HRMS (ESI) calcd for C₄₅H₄₇N₈O₆ [M+H]⁺: 795.3613, found, 795.3622.

Compound Example 122: synthesis of 8-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS219003)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS151019) was used to prepare SIAIS219003 (yellow solid, 6.6 mg, 38%). ¹H NMR (500 MHz, DMSO) δ 12.69 (s, 1H), 11.09 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.33 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.66 (s, 1H), 5.06 (dd, J = 12.8, 5.6 Hz, 1H), 3.26 - 3.18 (m, 6H), 2.78 - 2.68 (m, 10H), 2.40 (s, 4H), 2.07 - 1.99 (m, 2H), 1.89 - 1.78 (m, 6H), 1.75 (s, 6H), 1.61 (t, J = 10.4 Hz, 2H), 1.27 (t, J = 11.8 Hz, 5H). HRMS (ESI) calcd for C₄₇H₅₁N₈O₆ [M+H]⁺: 823.3926, found, 823.5145.

Compound Example 123: synthesis of 8-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. (SIAIS219004)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS151027) was used to prepare SIAIS219004 (yellow solid, 7.1 mg, 40%). ¹H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 11.08 (s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.31 (s, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.58 (s, 1H), 5.07 (dd, J = 12.8, 5.6 Hz, 1H), 3.24 - 3.13 (m, 6H), 2.75 - 2.65 (m, 10H), 2.36 (s, 4H), 2.05 - 1.97 (m, 2H), 1.86 - 1.77 (m, 6H), 1.73 (s, 6H), 1.60 (t, J = 10.4 Hz, 2H), 1.25-1.20 (m, 9H). HRMS (ESI) calcd for C₄₉H₅₅N₈O₆ [M+H]⁺:851.4239, found, 851.5517.

Compound Example 124: synthesis of (2S,4R)-1-((S)-2-(6-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS219015)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS074013) was used to prepare SIAIS219015 (yellow solid, 10.2 mg, 48%). ¹H NMR (500 MHz, DMSO) δ 12.79 (s, 1H), 10.63 (s, 1H), 8.98 (s, 1H), 8.57 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.40 - 7.34 (m, 3H), 4.57 - 4.50 (m, 2H), 4.47 - 4.40 (m, 2H), 4.35 (s, 1H), 4.22 (d, J = 11.5 Hz, 1H), 4.09 (d, J = 16.2 Hz, 1H), 3.70 - 3.62 (m, 2H), 3.54 (d, J = 16.2 Hz, 3H), 3.14 (d, J = 9.2 Hz, 1H), 3.02 (d, J = 18.4 Hz, 2H), 2.81 (t, J = 10.6 Hz, 2H), 2.74 - 2.68 (m, 2H), 2.44 (s, 3H), 2.40 - 2.35 (m, 2H), 2.32 - 2.25 (m, 1H), 2.19 (t, J = 14.0 Hz, 3H), 2.04-1.99 (m, 2H), 1.93-1.88 (m, 3H), 1.76 (s, 6H), 1.55 - 1.46 (m, 4H), 1.30-1.23 (m, 5H), 0.94 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₂N₉O₆S [M+H]⁺:1022.5321, found, 1022.4607.

Compound Example 125: synthesis of (2S,4R)-1-((S)-2-(10-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS219016)

According to the procedures for the preparation of Compound Example 1, Alectinib Analogue C and intermediate LM (SIAIS074019) was used to prepare SIAIS219016 (yellow solid, 9.8 mg, 43%). ¹H NMR (500 MHz, MeOD) δ 9.86 (s, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 7.57-7.54 (m, 5H), 7.43 (s, 1H), 4.64 (s, 1H), 4.59-4.53 (m, 3H), 4.41 (d, J = 15.7 Hz, 1H), 4.27 (s, 1H), 3.91 (d, J = 11.1 Hz, 1H), 3.81 (dd, J = 11.0, 3.8 Hz, 1H), 3.72 (s, 2H), 3.43 (d, J = 11.2 Hz, 3H), 3.15 (d, J = 12.9 Hz, 2H), 2.99 (t, J = 11.4 Hz, 2H), 2.81 (q, J = 7.5 Hz, 2H), 2.59 (s, 3H), 2.47 (t, J = 7.4 Hz, 2H), 2.39 - 2.20 (m, 6H), 2.10-2.04 (m, 4H), 1.80 (s, 6H), 1.62 (d, J = 6.2 Hz, 4H), 1.35 (t, J = 7.4 Hz, 12H), 1.04 (s, 9H). HRMS (ESI) calcd for C₆₂H₈₀N₉O₆S [M+H]⁺:1078.5947, found, 1078.5193.

Compound Example 126: synthesis of 4-((2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151031)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151001) was used to prepare SIAIS151031 (yellow solid, 20.8 mg, 62%). ¹H NMR (500 MHz, MeOD) δ 8.45 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H), 7.93 (dd, J = 8.0, 1.5 Hz, 1H), 7.76 (s, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.07 (dd, J = 8.4, 7.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.77 (d, J = 2.2 Hz, 1H), 5.00 - 4.94 (m, 1H), 4.70 (d, J = 13.0 Hz, 1H), 4.58 (s, 1H), 4.56 - 4.50 (m, 1H), 4.16 (d, J = 13.4 Hz, 1H), 3.90 - 3.77 (m, 2H), 3.73 -3.70 (m, 2H), 3.52 - 3.49 (m, 2H), 3.22 - 3.13 (m, 1H), 3.00 - 2.93 (m, 1H), 2.81 - 2.59 (m, 6H), 2.13 (d, J = 1.0 Hz, 3H), 2.03 - 1.95 (m, 1H), 1.76 (d, J = 13.1 Hz, 2H), 1.67 - 1.54 (m, 2H), 1.28 - 1.25 (m, 12H). HRMS (ESI) calcd for C₄₆H₅₄ClN₈O₉S [M+H]⁺: 929.3418, found, 929.2502.

Compound Example 127: synthesis of 4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl) amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151023)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151004) was used to prepare SIAIS151023 (yellow solid, 32.8 mg, 94%). ¹H NMR (500 MHz, MeOD) δ 8.45 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.74 (s, 1H), 7.69 - 7.66 (m, 1H), 7.51 - 7.47 (m, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.02 (dd, J = 8.5, 4.0 Hz, 1H), 7.00 (d, J = 7.0 Hz, 2H), 6.79 (s, 1H), 5.01 (dd, J = 12.5, 5.5 Hz, 1H), 4.69 (d, J = 13.1 Hz, 1H), 4.59 - 4.54 (m, 1H), 4.12 (d, J = 13.0 Hz, 1H), 3.81 - 3.74 (m, 2H), 3.71 - 3.60 (m, 6H), 3.45 - 3.41 (m, 2H), 3.36 - 3.32 (m, 1H), 3.21 - 3.13 (m, 1H), 2.99 - 2.93 (m, 1H), 2.84 - 2.64 (m, 5H), 2.63 - 2.55 (m, 1H), 2.13 (s, 3H), 2.07 - 2.03 (m, 1H), 1.79 - 1.71 (m, 2H), 1.67 - 1.52 (m, 2H), 1.31 - 1.28 (m, 6H), 1.26 (d, J = 6.8 Hz, 6H). HRMS (ESI) calcd for C₄₈H₅₈ClN₈O₁₀S [M+H]⁺: 973.3680, found, 973.3685.

Compound Example 128: synthesis of 4-((2-(2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy) ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151028)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151005) was used to prepare SIAIS151028 (yellow solid, 32.4 mg, 89%). ¹H NMR (500 MHz, MeOD) δ 8.45 (d, J = 8.2 Hz, 1H), 8.15 (s, 1H), 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.76 (s, 1H), 7.70 - 7.64 (m, 1H), 7.50 (dd, J = 8.4, 7.2 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 7.2 Hz, 2H), 6.80 (s, 1H), 5.02 (dd, J = 12.5, 5.5 Hz, 1H), 4.70 (d, J = 13.0 Hz, 1H), 4.61 - 4.54 (m, 1H), 4.14 (d, J = 11.9 Hz, 1H), 3.82 - 3.71 (m, 2H), 3.67 - 3.59 (m, 10H), 3.43 (t, J = 5.4 Hz, 2H), 3.35 - 3.31 (m, 1H), 3.22 - 3.16 (m, 1H), 3.01 - 2.95 (m, 1H), 2.83 (s, 1H), 2.81 - 2.67 (m, 4H), 2.63 - 2.56 (m, 1H), 2.15 (s, 3H), 2.10 - 2.04 (m, 1H), 1.80 - 1.75 (m, 2H), 1.70 - 1.52 (m, 2H), 1.29 (t, J = 6.0 Hz, 6H), 1.25 (d, J = 6.8 Hz, 6H). HRMS (ESI) calcd for C₅₀H₆₂ClN₈O₁₁S [M+H]⁺: 1017.3942, found, 1017.3457.

Compound Example 129: synthesis of 4-((18-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151029)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151007) was used to prepare SIAIS151029 (yellow solid, 31.6 mg, 80%). ¹H NMR (500 MHz, MeOD) δ 8.45 (d, J = 8.3 Hz, 1H), 8.14 (s, 1H), 7.93 - 7.90 (m, 1H), 7.76 (s, 1H), 7.68 - 7.64 (m, 1H), 7.51 (dd, J = 8.5, 7.1 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.03 (dd, J = 12.8, 7.8 Hz, 2H), 6.80 (s, 1H), 5.02 (dd, J = 12.6, 5.5 Hz, 1H), 4.70 (d, J = 13.4 Hz, 1H), 4.61 - 4.55 (m, 2H), 4.15 (d, J = 14.0 Hz, 1H), 3.79 - 3.74 (m, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.62 - 3.55 (m, 16H), 3.46 - 3.43 (m, 2H), 3.24 - 3.18 (m, 1H), 3.04 - 2.94 (m, 1H), 2.83 - 2.61 (m, 6H), 2.15 (s, 3H), 2.10 - 2.04 (m, 1H), 1.82 - 1.76 (m, 2H), 1.69 - 1.53 (m, 2H), 1.30 (t, J = 6.1 Hz, 6H), 1.26 (s, 3H), 1.24 (s, 3H). HRMS (ESI) calcd for C₅₄H₇₀ClN₈O₁₃S [M+H]⁺: 1105.4466, found, 1105.3969.

Compound Example 130: synthesis of 4-((2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151037)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151025) was used to prepare SIAIS151037 (yellow solid, 20.1 mg, 64%). ¹H NMR (500 MHz, DMSO) δ 11.11 (s, 1H), 9.46 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.53 (s, 1H), 7.40 - 7.33 (m, 1H), 7.20 - 7.15 (m, 2H), 7.08 (d, J = 7.0 Hz, 1H), 6.86 (s, 1H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.60 - 4.54 (m, 2H), 4.35 - 4.13 (m, 2H), 4.05 (d, J = 13.0 Hz, 1H), 3.48 - 3.40 (m, 1H), 3.24 - 3.14 (m, 1H), 3.01 - 2.85 (m, 2H), 2.77 (t, J = 12.1 Hz, 1H), 2.63 - 2.52 (m, 2H), 2.17 (s, 3H), 2.08 - 2.00 (m, 1H), 1.74 - 1.71 (m, 3H), 1.59 - 1.48 (m, 1H), 1.20 - 1.15 (m, 12H). HRMS (ESI) calcd for C₄₃H₄₈ClN₈O₈S [M+H]⁺: 871.2999, found, 871.0255.

Compound Example 131: synthesis of 4-((3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151034)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151026) was used to prepare SIAIS151034 (yellow solid, 27.1 mg, 85%). ¹H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.45 (s, 1H), 8.46 (d, J = 8.1 Hz, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.83 (dd, J = 8.0, 1.5 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.52 (s, 1H), 7.40 - 7.30 (m, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.87 - 6.77 (m, 2H), 5.04 (dd, J = 12.8, 5.5 Hz, 1H), 4.65 - 4.52 (m, 2H), 3.98 (d, J = 12.6 Hz, 1H), 3.57 (dd, J = 12.4, 6.1 Hz, 2H), 3.46 - 3.41 (m, 1H), 3.11 (t, J = 11.8 Hz, 1H), 2.96 - 2.83 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68 - 2.52 (m, 3H), 2.14 (s, 3H), 2.05 - 1.97 (m, 1H), 1.71 - 1.67 (m, 2H), 1.64 - 1.56 (m, 1H), 1.52 - 1.43 (m, 1H), 1.21 - 1.13 (m, 12H). HRMS (ESI) calcd for C₄₄H₅₀ClN₈O₈S [M+H]⁺: 885.3155, found, 885.2667.

Compound Example 132: synthesis of 4-((4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151035)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151019) was used to prepare SIAIS151035 (yellow solid, 21.5 mg, 67%). ¹H NMR (500 MHz, MeOD) δ 8.46 (d, J = 8.3 Hz, 1H), 8.15 (s, 1H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (s, 1H), 7.70 - 7.64 (m, 1H), 7.56 (dd, J = 8.5, 7.1 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 7.1 Hz, 1H), 6.79 (s, 1H), 5.05 - 5.01 (m, 1H), 4.71 (d, J = 11.6 Hz, 1H), 4.59 - 4.52 (m, 1H), 4.09 (d, J = 12.5 Hz, 1H), 3.47 - 3.41 (m, 2H), 3.36 - 3.33 (m, 1H), 3.24 - 3.16 (m, 1H), 3.01 - 2.95 (m, 1H), 2.86 - 2.78 (m, 1H), 2.77 - 2.66 (m, 3H), 2.64 - 2.49 (m, 2H), 2.15 (s, 3H), 2.10 - 1.96 (m, 3H), 1.79 (d, J = 13.1 Hz, 2H), 1.63 - 1.49 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H), 1.26 (d, J = 6.8 Hz, 6H). HRMS (ESI) calcd for C₄₅H₅₂ClN₈O₈S [M+H]⁺: 899.3312, found, 899.0450.

Compound Example 133: synthesis of 4-((5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151036)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151020) was used to prepare SIAIS151036 (yellow solid, 31.5 mg, 96%). ¹H NMR (500 MHz, MeOD) δ 8.46 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.77 (s, 1H), 7.74 - 7.66 (m, 1H), 7.55 (dd, J = 8.5, 7.2 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.08 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.1 Hz, 1H), 6.79 (s, 1H), 5.03 - 4.95 (m, 1H), 4.69 (d, J = 11.6 Hz, 1H), 4.61 - 4.53 (m, 1H), 4.08 - 4.04 (m, 1H), 3.46 - 3.32 (m, 3H), 3.24 - 3.16 (m, 1H), 3.01 - 2.97 (m, 1H), 2.82 - 2.61 (m, 4H), 2.57 - 2.44 (m, 2H), 2.15 (s, 3H), 2.05 - 1.99 (m, 1H), 1.82 - 1.72 (m, 6H), 1.65 - 1.51 (m, 2H), 1.31 - 1.27 (m, 6H), 1.26 (d, J = 6.8 Hz, 6H). HRMS (ESI) calcd for C₄₆H₅₄ClN₈O₈S [M+H]⁺: 913.3468, found, 913.0576.

Compound Example 134: synthesis of 4-((6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151043)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151027) was used to prepare SIAIS151043 (yellow solid, 26.3 mg, 79%). ¹H NMR (500 MHz, MeOD) δ 8.26 (d, J = 8.3 Hz, 1H), 8.09 (s, 1H), 7.88 (dd, J = 8.0, 1.4 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.45 (dd, J = 8.5, 7.1 Hz, 1H), 7.40 - 7.36 (m, 2H), 6.95 (dd, J = 13.9, 7.8 Hz, 2H), 6.76 (d, J = 2.2 Hz, 1H), 4.95 - 4.90 (m, 1H), 4.63 - 4.59 (m, 1H), 4.52 - 4.47 (m, 1H), 4.00 (d, J = 13.1 Hz, 1H), 3.27 (t, J = 6.9 Hz, 3H), 3.14 - 3.08 (m, 1H), 2.95 - 2.89 (m, 1H), 2.75 - 2.54 (m, 4H), 2.38 (t, J = 7.4 Hz, 2H), 2.09 (s, 3H), 2.01 - 1.93 (m, 1H), 1.74 - 1.66 (m, 2H), 1.66 - 1.58 (m, 4H), 1.55 - 1.38 (m, 4H), 1.17 - 1.15 (m, 12H). HRMS (ESI) calcd for C₄₇H₅₆ClN₈O₈S [M+H]⁺: 927.3625, found, 927.0642.

Compound Example 135: synthesis of (2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151042)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151010) was used to prepare SIAIS151042 (white solid, 36.8 mg, 91%). ¹H NMR (500 MHz, MeOD) δ 8.91 (d, J = 1.6 Hz, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.99 (dd, J = 8.0, 1.4 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.53 - 7.49 (m, 1H), 7.47 - 7.34 (m, 5H), 6.86 (d, J = 6.2 Hz, 1H), 4.72 - 4.53 (m, 4H), 4.51 - 4.31 (m, 5H), 4.13 - 4.01 (m, 3H), 3.88 - 3.86 (m, 1H), 3.83 - 3.69 (m, 5H), 3.39 - 3.34 (m, 1H), 3.24 - 3.16 (m, 1H), 3.07 - 2.97 (m, 1H), 2.79 - 2.71 (m, 1H), 2.47 - 2.45 (m, 3H), 2.26 - 2.14 (m, 1H), 2.18 (s, 3H), 2.12 - 2.04 (m, 1H), 1.82 - 1.77 (m, 2H), 1.73 - 1.53 (m, 2H), 1.27 - 1.24 (m, 12H), 1.05 (d, J = 4.5 Hz, 9H). HRMS (ESI) calcd for C₅₆H₇₃ClN₉O₁₀S₂ [M+H]⁺: 1130.4605, found, 1130.0737.

Compound Example 136: synthesis of (2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151038)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151002) was used to prepare SIAIS151038 (white solid, 39.4 mg, 95%). ¹H NMR (500 MHz, MeOD) δ 8.92 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 7.2 Hz, 1H), 8.19 (s, 1H), 7.99 (dd, J = 8.0, 1.5 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.48 - 7.35 (m, 5H), 6.87 (s, 1H), 4.72 - 4.69 (m, 1H), 4.67 - 4.64 (m, 1H), 4.64 - 4.47 (m, 4H), 4.35 (d, J = 15.3 Hz, 1H), 4.16 (d, J = 12.2 Hz, 1H), 3.88 (d, J = 11.1 Hz, 1H), 3.82 - 3.67 (m, 5H), 3.66 - 3.60 (m, 4H), 3.40 - 3.35 (m, 1H), 3.25 - 3.19 (m, 1H), 3.03 (t, J = 10.9 Hz, 1H), 2.77 - 2.65 (m, 3H), 2.58 - 2.52 (m, 1H), 2.50 - 2.43 (m, 4H), 2.24 - 2.18 (m, 1H), 2.20 (s, 3H), 2.11 - 2.05 (m, 1H), 1.86 - 1.75 (m, 2H), 1.71 - 1.52 (m, 2H), 1.28 - 1.24 (m, 12H), 1.03 (s, 9H). HRMS (ESI) calcd for C₅₈H₇₇ClN₉O₁₀S₂ [M+H]⁺: 1158.4918, found, 1158.4604.

Compound Example 137: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151039)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151003) was used to prepare SIAIS151039 (white solid, 40.2 mg, 93%). ¹H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.32 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 7.99 (dd, J = 8.0, 1.5 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.48 - 7.36 (m, 5H), 6.88 (s, 1H), 4.74 - 3.70 (m, 1H), 4.66 - 4.47 (m, 5H), 4.35 (d, J = 15.5 Hz, 1H), 4.16 (d, J = 12.6 Hz, 1H), 3.88 (d, J = 11.1 Hz, 1H), 3.81 - 3.76 (m, 3H), 3.74 - 3.67 (m, 2H), 3.63 - 3.58 (m, 8H), 3.40 - 3.35 (m, 1H), 3.23 (t, J = 12.9 Hz, 1H), 3.06 - 3.00 (m, 1H), 2.78 - 2.64 (m, 3H), 2.59 - 2.53 (m, 1H), 2.50 - 2.42 (m, 4H), 2.25 - 2.17 (m, 1H), 2.20 (s, 3H), 2.11 - 2.05 (m, 1H), 1.80 (t, J = 15.3 Hz, 2H), 1.73 - 1.53 (m, 2H), 1.28 - 1.24 (m, 12H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₀H₈₁ClN₉O₁₁S₂ [M+H]⁺: 1202.5180, found, 1203.4829.

Compound Example 138: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151040)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151008) was used to prepare SIAIS151040 (white solid, 34.3 mg, 77%). ¹H NMR (500 MHz, MeOD) δ 8.94 (s, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.20 (s, 1H), 7.99 (dd, J = 8.0, 1.5 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.48 - 7.41 (m, 4H), 7.36 (s, 1H), 6.89 (s, 1H), 4.72 (d, J = 13.5 Hz, 1H), 4.65 - 4.47 (m, 5H), 4.35 (d, J = 15.5 Hz, 1H), 4.17 (d, J = 13.7 Hz, 1H), 3.88 (d, J = 11.1 Hz, 1H), 3.81 - 3.76 (m,3H), 3.74 - 3.67 (m, 2H), 3.63 - 3.56 (m, 14H), 3.41 - 3.35 (m, 1H), 3.23 (t, J = 12.3 Hz, 1H), 3.07 - 3.01 (m, 1H), 2.80 - 2.64 (m, 3H), 2.59 - 2.53 (m, 1H), 2.49 - 2.45 (m, 4H), 2.25 - 2.18 (m, 1H), 2.20 (s, 3H), 2.11 - 2.05 (m, 1H), 1.80 (t, J = 15.2 Hz, 2H), 1.74 - 1.55 (m, 2H), 1.28 - 1.24 (m, 12H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₂H₈₅ClN₉O₁₂S₂ [M+H]⁺: 1246.5442, found, 1246.5029.

Compound Example 139: synthesis of (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS151041)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS151009) was used to prepare SIAIS151041 (white solid, 40 mg, 86%). ¹H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.32 (d, J = 7.5 Hz, 1H), 8.19 (s, 1H), 7.99 (dd, J = 8.0, 1.5 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.43 (ddd, J = 19.0, 15.8, 9.5 Hz, 5H), 6.89 (s, 1H), 4.72 (d, J = 13.5 Hz, 1H), 4.66 - 4.48 (m, 5H), 4.37 - 4.33 (m, 1H), 4.17 (d, J = 13.5 Hz, 1H), 3.88 (d, J = 11.1 Hz, 1H), 3.84 - 3.76 (m, 3H), 3.75 - 3.67 (m, 2H), 3.63 - 3.58 (m, 16H), 3.40 - 3.35 (m, 1H), 3.23 (t, J = 12.0 Hz, 1H), 3.07 - 3.01 (m, 1H), 2.78 - 2.65 (m, 3H), 2.61 - 2.52 (m, 1H), 2.50 - 2.42 (m, 1H), 2.47 (s, 3H), 2.24 - 2.18 (m, 4H), 2.10 - 2.05 (m, 1H), 1.81 (t, J = 15.2 Hz, 2H), 1.74 - 1.52 (m, 2H), 1.28 - 1.24 (m, 12H), 1.03 (s, 9H). HRMS (ESI) calcd for C₆₄H₈₉ClN₉O₁₃S₂ [M+H]⁺: 1290.5704, found, 1290.5117.

Compound Example 140: synthesis of (2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074017)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074011) was used to prepare SIAIS074017 (white solid, 72 mg, 75%). ¹H NMR (500 MHz, MeOD) δ 8.86 (d, J = 1.7 Hz, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (s, 1H), 7.69 - 7.64 (m, 1H), 7.48 - 7.44 (m, 2H), 7.42 - 7.40 (m, 2H), 7.38 - 7.35 (m, 1H), 6.80 (d, J = 7.1 Hz, 1H), 4.68 (d, J = 11.6 Hz, 1H), 4.63 (d, J = 7.4 Hz, 1H), 4.61 - 4.53 (m, 3H), 4.53 - 4.44 (m, 2H), 4.36 (dd, J = 15.4, 4.3 Hz, 1H), 4.12 (d, J = 13.5 Hz, 1H), 3.90 (d, J = 11.1 Hz, 1H), 3.80 (dd, J = 11.0, 3.8 Hz, 1H), 3.24 - 3.19 (m, 1H), 3.03 - 2.97 (m, 1H), 2.80 - 2.68(m, 3H), 2.67 - 2.53 (m, 2H), 2.47 (d, J = 3.0 Hz, 3H), 2.25 - 2.18 (m, 1H), 2.16 (s, 3H), 2.11 - 2.05 (m, 1H), 1.83 - 1.76 (m, 2H), 1.71 - 1.63 (m, 1H), 1.59 - 1.51 (m, 1H), 1.32 - 1.29 (m, 6H), 1.25 (d, J = 6.8 Hz, 6H), 1.05 (s, 9H). HRMS (ESI) calcd for C₅₄H₆₉ClN₉O₈S₂ ⁺ [M+H]⁺: 1070.4394; found, 1070.4352.

Compound Example 141: synthesis of (2S,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074018)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074012) was used to prepare SIAIS074018 (white solid, 25.2 mg, 65%). ¹H NMR (500 MHz, CDCl₃) δ 10.63 - 10.18 (m, 1H), 9.28 - 8.52 (m, 3H), 8.42 (d, J = 7.9 Hz, 1H), 8.09 - 7.86 (m, 1H), 7.59 - 7.43 (m, 1H), 7.35 (t, J = 15.5 Hz, 6H), 7.13 (s, 1H), 6.73 (d, J = 14.8 Hz, 1H), 6.27 (s, 1H), 4.76 (s, 1H), 4.52 (d, J = 24.2 Hz, 3H), 4.34 (d, J = 13.3 Hz, 1H), 4.06 (d, J = 72.7 Hz, 2H), 3.75 - 3.45 (m, 1H), 3.28 - 3.08 (m, 2H), 2.88 (d, J = 43.8 Hz, 2H), 2.67 (s, 3H), 2.60 - 2.25 (m, 7H), 2.19 (s, 4H), 2.10 - 1.72 (m, 4H), 1.57 (s, 2H), 1.32 (dd, J = 42.6, 36.2 Hz, 13H), 1.11 - 0.82 (m, 9H). HRMS (ESI) calcd for C₅₅H₇₁ClN₉O₈S₂ ⁺ [M+H]⁺: 1084.4550; found, 1084.4549.

Compound Example 142: synthesis of (2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074021)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074013) was used to prepare SIAIS074021 (white solid, 27.3 mg, 69%). ¹H NMR (500 MHz, CDCl₃) δ 10.27 (s, 1H), 10.23 - 10.07 (m, 1H), 8.83 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 7.99 (s, 1H), 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.40 (dd, J = 15.4, 6.9 Hz, 1H), 7.38 - 7.28 (m, 4H), 6.73 (d, J = 3.8 Hz, 1H), 6.42 (dd, J = 25.8, 8.5 Hz, 1H), 5.35 (t, J = 4.8 Hz, 1H), 4.88 - 4.70 (m, 2H), 4.59 (dd, J = 15.0, 6.7 Hz, 1H), 4.51 (dd, J = 11.9, 5.4 Hz, 2H), 4.34 (dd, J = 14.9, 5.1 Hz, 1H), 4.13 (d, J = 11.8 Hz, 1H), 4.00 (d, J = 12.3 Hz, 1H), 3.80 - 3.42 (m, 6H), 3.26 - 3.09 (m, 2H), 2.92 (t, J = 12.0 Hz, 1H), 2.65 (s, 1H), 2.57 (ddd, J = 16.5, 8.1, 4.0 Hz, 1H), 2.53 (s, 2H), 2.39 (s, 1H), 2.34 - 2.21 (m, 2H), 2.21 - 2.12 (m, 3H), 2.04 - 1.97 (m, 1H), 1.88 - 1.77 (m, 2H), 1.75 - 1.47 (m, 5H), 1.34 - 1.23 (m, 12H), 1.01 - 0.75 (m, 7H). HRMS (ESI) calcd for C₅₆H₇₃ClN₉O₈S₂ ⁺ [M+H]⁺: 1098.4707; found, 1098.6188.

Compound Example 143: synthesis of (2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074022)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074014) was used to prepare SIAIS074022 (white solid, 29.5 mg, 74%). ¹H NMR (500 MHz, CDCl₃) δ 10.11 (s, 1H), 9.63 (s, 1H), 8.76 (s, 1H), 8.48 (d, J = 8.3 Hz, 1H), 8.02 (s, 1H), 7.92 (dd, J = 7.9, 1.5 Hz, 1H), 7.58 (s, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.40 - 7.32 (m, 4H), 7.29 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 9.6 Hz, 1H), 6.19 (d, J = 6.8 Hz, 1H), 4.77 (dd, J = 19.4, 11.3 Hz, 2H), 4.64 - 4.46 (m, 4H), 4.34 (dd, J = 15.0, 5.1 Hz, 2H), 4.05 (dd, J = 56.9, 11.8 Hz, 3H), 3.60 (dd, J = 11.3, 3.2 Hz, 1H), 3.27 - 3.18 (m, 1H), 3.14 (dd, J = 19.6, 13.0 Hz, 1H), 2.91 (t, J = 10.7 Hz, 1H), 2.69 - 2.58 (m, 1H), 2.57 - 2.49 (m, 3H), 2.45 - 2.31 (m, 2H), 2.31 - 2.11 (m, 6H), 1.80 (dd, J = 33.7, 17.8 Hz, 2H), 1.74 - 1.48 (m, 6H), 1.43 - 1.23 (m, 15H), 1.01 - 0.82 (m, 9H). HRMS (ESI) calcd for C₅₇H₇₅ClN₉O₈S₂ ⁺ [M+H]⁺ : 1112.4863, found, 1112.6343.

Compound Example 144: synthesis of (2S,4R)-1-((S)-2-(8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074008)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074015) was used to prepare SIAIS074008 (white solid, 30.1 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ 9.89 (s, 1H), 8.92 (s, 1H), 8.71 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 17.2 Hz, 1H), 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.74 (s, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.37 (p, J = 8.3 Hz, 3H), 7.29 (dd, J = 11.4, 4.4 Hz, 1H), 6.70 (d, J = 4.5 Hz, 1H), 6.18 - 6.05 (m, 1H), 5.35 (dd, J = 12.6, 7.8 Hz, 1H), 4.77 (dd, J = 20.6, 12.4 Hz, 2H), 4.62 - 4.48 (m, 3H), 4.35 (dt, J = 14.9, 5.3 Hz, 1H), 4.13 (d, J = 11.3 Hz, 1H), 3.98 (d, J = 12.5 Hz, 1H), 3.59 (dd, J = 11.3, 3.3 Hz, 1H), 3.23 (dt, J = 13.7, 6.9 Hz, 1H), 3.14 (dd, J = 19.2, 12.6 Hz, 1H), 3.07 - 2.67 (m, 5H), 2.67 - 2.59 (m, 1H), 2.59 - 2.48 (m, 3H), 2.41 - 2.30 (m, 2H), 2.28 - 2.09 (m, 5H), 2.04 - 1.97 (m, 1H), 1.87 - 1.75 (m, 2H), 1.70 - 1.46 (m, 5H), 1.39 - 1.22 (m, 14H), 0.96 - 0.84 (m, 6H). HRMS (ESI) calcd for C₅₈H₇₇ClN₉O₈S₂ ⁺ [M+H]⁺: 1126.5020, found, 1126.6505.

Compound Example 145: synthesis of (2S,4R)-1-((S)-2-(9-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074024)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074016) was used to prepare SIAIS074024 (white solid, 31.2 mg, 76%). ¹H NMR (500 MHz, MeOD) δ 8.90 (t, J = 2.2 Hz, 1H), 8.35 (d, J = 7.5 Hz, 1H), 8.19 (s, 1H), 7.98 (dd, J = 8.0, 1.4 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.53 - 7.38 (m, 6H), 6.86 (d, J = 1.7 Hz, 1H), 4.70 (d, J = 12.8 Hz, 1H), 4.66 - 4.47 (m, 5H), 4.36 (d, J = 15.5 Hz, 1H), 4.11 (d, J = 13.5 Hz, 1H), 3.91 (d, J = 11.0 Hz, 1H), 3.80 (dd, J = 10.9, 3.8 Hz, 1H), 3.36 (td, J = 13.3, 6.4 Hz, 2H), 3.23 (t, J = 13.1 Hz, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.72 (t, J = 13.2 Hz, 1H), 2.51 - 2.39 (m, 5H), 2.35 - 2.16 (m, 7H), 2.12 - 1.99 (m, 2H), 1.84 (d, J = 12.9 Hz, 1H), 1.78 (d, J = 12.8 Hz, 1H), 1.69 - 1.49 (m, 7H), 1.32 - 1.21 (m, 14H), 1.02 (s, 9H). HRMS (ESI) calcd for C₅₉H₇₉ClN₉O₈S₂ ⁺ [M+H]⁺ : 1140.5176, found, 1140.5167.

Compound Example 146: synthesis of (2S,4R)-1-((S)-2-(10-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074025)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074019) was used to prepare SIAIS074025 (white solid, 31.5 mg, 76%). ¹H NMR (500 MHz, MeOD) δ 8.90 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H), 7.97 (dd, J = 8.0, 1.4 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.50 - 7.40 (m, 6H), 6.85 (s, 1H), 4.70 (d, J = 13.1 Hz, 1H), 4.66 - 4.44 (m, 6H), 4.38 - 4.33 (m, 1H), 4.11 (d, J = 13.6 Hz, 1H), 3.90 (d, J = 11.0 Hz, 1H), 3.80 (dd, J = 10.9, 3.8 Hz, 1H), 3.39 - 3.32 (m, 2H), 3.23 (t, J = 12.3 Hz, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.72 (t, J = 12.3 Hz, 1H), 2.50 - 2.41 (m, 5H), 2.34 - 2.20 (m, 4H), 2.19 (s, 3H), 2.14 - 1.97 (m, 2H), 1.81 (dd, J = 28.9, 13.0 Hz, 3H), 1.67 - 1.50 (m, 7H), 1.28 (dd, J = 6.0, 2.0 Hz, 8H), 1.25 (d, J = 6.8 Hz, 6H), 1.02 (d, J = 13.8 Hz, 9H). HRMS (ESI) calcd for C₆₀H₆₁ClN₉O₈S₂ ⁺ [M+H]⁺ : 1154.5333, found, 1154.2914.

Compound Example 147: synthesis of (2S,4R)-1-((S)-2-(11-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-11-oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. (SIAIS074026)

According to the procedures for the preparation of Compound Example 1, Ceritinib and intermediate LM (SIAIS074020) was used to prepare SIAIS074026 (white solid, 32.0 mg, 76%). ¹H NMR (500 MHz, MeOD) δ 8.89 (s, 1H), 8.39 (d, J = 8.3 Hz, 1H), 8.17 (s, 1H), 7.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.51 - 7.37 (m, 5H), 6.84 (s, 1H), 4.71 (d, J = 13.0 Hz, 1H), 4.67 - 4.46 (m, 5H), 4.35 (dd, J = 15.3, 7.4 Hz, 1H), 4.11 (d, J = 13.3 Hz, 1H), 3.90 (d, J = 11.1 Hz, 1H), 3.80 (dd, J = 10.9, 3.9 Hz, 1H), 3.39 - 3.32 (m, 2H), 3.23 (t, J = 12.2 Hz, 1H), 3.02 (t, J = 12.0 Hz, 1H), 2.72 (t, J = 12.2 Hz, 1H), 2.50 - 2.40 (m, 5H), 2.34 - 2.15 (m, 6H), 2.12 - 2.00 (m, 2H), 1.83 (t, J = 11.2 Hz, 1H), 1.78 (d, J = 13.2 Hz, 1H), 1.67 - 1.51 (m, 6H), 1.36 (s, 3H), 1.29 (dd, J = 6.0, 2.0 Hz, 8H), 1.25 (d, J = 6.8 Hz, 6H), 1.02 (d, J = 13.3 Hz, 9H). HRMS (ESI) calcd for C₆₁H₆₃C1N₉O₈S₂ ⁺ [M+H]⁺: 1168.5489, found, 1168.3009.

Compound Example 148: synthesis of 4-((2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151049)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151001) was used to prepare SIAIS151049 (yellow solid, 21.4 mg, 59%). ¹H NMR (500 MHz, MeOD) δ 7.84 (dd, J = 10.1, 6.3 Hz, 1H), 7.55 - 7.49 (m, 3H), 7.48 - 7.43 (m, 1H), 7.35 - 7.26 (m, 1H), 7.12 - 7.05 (m, 1H), 7.05 - 6.99 (m, 1H), 6.90 (dd, J = 12.7, 6.8 Hz, 1H), 6.36 - 6.28 (m, 1H), 5.02 - 4.97 (m, 1H), 4.65 (d, J = 13.5 Hz, 1H), 4.44 - 4.38 (m, 1H), 4.20 (d, J = 13.3 Hz, 1H), 3.91 - 3.77 (m, 2H), 3.75 - 3.68 (m, 2H), 3.51 - 3.45 (m, 2H), 3.29 - 3.21 (m, 1H), 2.86 - 2.77 (m, 3H), 2.74-2.60 (m, 3H), 2.12 (d, J = 11.7 Hz, 2H), 2.08 - 2.01 (m, 1H), 1.99 - 1.84 (m, 5H). HRMS (ESI) calcd for C₃₉H₄₀Cl₂FN₈O₇ ⁺ [M+ H]⁺: 821.2376; found, 821.2334.

Compound Example 149: synthesis of 4-((2-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl) ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151050)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151004) was used to prepare SIAIS151050 (yellow solid, 31.8 mg, 83%). ¹H NMR (500 MHz, MeOD) δ 7.88 (d, J = 5.5 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.55 - 7.49 (m, 2H), 7.48 - 7.41 (m, 1H), 7.31 - 7.27 (m, 1H), 7.08 (d, J = 1.7 Hz, 1H), 6.98 - 6.90 (m, 2H), 6.32 - 6.27 (m, 1H), 5.06 - 4.99 (m, 1H), 4.64 (d, J = 13.2 Hz, 1H), 4.44 - 4.36 (m, 1H), 4.15 (d, J = 13.7 Hz, 1H), 3.85 - 3.71 (m, 2H), 3.70 - 3.61 (m, 6H), 3.40 - 3.34 (m, 2H), 3.25 (t, J = 13.0 Hz, 1H), 2.90 - 2.66 (m, 5H), 2.60 - 2.52 (m, 1H), 2.14 - 2.05 (m, 3H), 2.01 - 1.83 (m, 5H). HRMS (ESI) calcd for C₄₁H₄₄Cl₂FN₈O₈ ⁺ [M+ H]⁺: 865.2638; found, 865.2602.

Compound Example 150: synthesis of 4-((2-(2-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151051)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151005) was used to prepare SIAIS151051 (yellow solid, 36.7 mg, 91%). ¹H NMR (500 MHz, MeOD) δ 7.91 (d, J = 1.6 Hz, 1H), 7.60 (s, 1H), 7.56 - 7.54 (m, 1H), 7.52 - 7.46 (m, 2H), 7.31 - 7.27 (t, J = 8.6 Hz, 1H), 7.12 - 7.08 (m, 1H), 7.01 - 6.92 (m, 2H), 6.33 - 6.27 (m, 1H), 5.07 - 5.01 (m, 1H), 4.63 (d, J = 11.1 Hz, 1H), 4.45 - 4.39 (m, 1H), 4.16 (d, J = 13.5 Hz, 1H), 3.80 - 3.70 (m, 2H), 3.66 - 3.59 (m, 10H), 3.45 - 3.34 (m, 2H), 3.29 - 3.24 (m, 1H), 2.87 - 2.64 (m, 5H), 2.61 - 2.52 (m, 1H), 2.19 - 2.06 (m, 3H), 2.03 - 1.83 (m, 5H). HRMS (ESI) calcd for C₄₃H₄₈Cl₂FN₈O₉ ⁺ [M+ H]⁺: 909.2900; found, 909.3068.

Compound Example 151: synthesis of 4-((15-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151060)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151006) was used to prepare SIAIS151060 (yellow solid, 27.7 mg, 65%). ¹H NMR (500 MHz, MeOD) δ 7.92 (s, 1H), 7.59 (d, J = 17.3 Hz, 2H), 7.52 - 7.42 (m, 2H), 7.29 (td, J= 8.7, 1.8 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 7.02 - 6.98 (m, 2H), 6.33 - 6.29 (m, 1H), 5.03 (dd, J = 12.8, 5.5 Hz, 1H), 4.62 (d, J = 13.2 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.16 (d, J = 13.4 Hz, 1H), 3.77 - 3.73 (m, 2H), 3.69 - 3.66 (m, 2H), 3.63 - 3.59 (m, 12H), 3.45 - 3.38 (m, 2H), 3.29 - 3.25 (m, 1H), 2.89 - 2.80 (m, 2H), 2.78 - 2.68 (m, 3H), 2.64 - 2.59 (m, 1H), 2.17 - 2.07 (m, 3H), 2.03 - 1.86 (m, 5H). HRMS (ESI) calcd for C₄₅H₅₂Cl₂FN₈O₁₀ ⁺ [M+ H]⁺: 953.3162; found, 953.4072.

Compound Example 152: synthesis of 4-((18-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151061)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151007) was used to prepare SIAIS151061 (yellow solid, 27.0 mg, 61%). ¹H NMR (500 MHz, MeOD) δ 7.93 (s, 1H), 7.60 (d, J = 14.4 Hz, 2H), 7.53 - 7.47 (m, 2H), 7.29 (t, J = 8.6 Hz, 1H), 7.11 (s, 1H), 7.02 - 6.99 (m, 2H), 6.34 - 6.28 (m, 1H), 5.03 (dd, J = 12.8, 5.5 Hz, 1H), 4.63 (d, J = 12.9 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.15 (d, J = 13.9 Hz, 1H), 3.77 - 3.73 (m, 2H), 3.72 - 3.66 (m, 2H), 3.63 (s, 3H), 3.62 - 3.55 (m, 13H), 3.44 - 3.41 (m, 2H), 3.29 - 3.25 (m, 1H), 2.87 - 2.59 (m, 6H), 2.20 - 2.06 (m, 3H), 2.01 - 1.84 (m, 5H). HRMS (ESI) calcd for C₄₇H₅₆Cl₂FN₈O₁₁ ⁺ [M+ H]⁺: 997.3424; found, 997.4381.

Compound Example 153: synthesis of 4-((2-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151083)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151025) was used to prepare SIAIS151083 (yellow solid, 18.4 mg, 54%). ¹H NMR (500 MHz, MeOD) δ 7.95 (s, 1H), 7.64 (s, 1H), 7.59 (d, J = 1.4 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.28 (t, J = 8.5 Hz, 1H), 7.15 (s, 1H), 7.05 (d, J = 7.1 Hz, 1H), 6.98 (dd, J = 8.5, 2.5 Hz, 1H), 6.34 (q, J = 6.6 Hz, 1H), 5.06 (dd, J = 12.5, 5.4 Hz, 1H), 4.64 (d, J = 13.5 Hz, 1H), 4.55 - 4.46 (m, 1H), 4.29 - 4.16 (m, 2H), 4.08 (d, J = 13.3 Hz, 1H), 3.35 - 3.31 (m, 1H), 2.95 (t, J = 12.6 Hz, 1H), 2.88 - 2.80 (m, 1H), 2.78 - 2.64 (m, 2H), 2.24 - 2.04 (m, 4H), 1.94 (d, J = 6.6 Hz, 4H). HRMS (ESI) calcd for C₃₆H₃₄Cl₂FN₈O₆ [M+ H]⁺: 763.1957; found, 763.1696.

Compound Example 154: synthesis of 4-((3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151084)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151026) was used to prepare SIAIS151084 (yellow solid, 22 mg, 64%). ¹H NMR (500 MHz, MeOD) δ 7.85 (s, 1H), 7.65 - 7.54 (m, 3H), 7.51 (dd, J = 8.9, 4.7 Hz, 1H), 7.29 (t, J = 8.6 Hz, 1H), 7.16 - 7.11 (m, 2H), 7.05 - 7.01 (m, 1H), 6.35 (q, J = 6.0 Hz, 1H), 5.06 - 4.97 (m, 1H), 4.65 (d, J = 11.5 Hz, 1H), 4.45 - 4.39 (m, 1H), 4.12 - 4.06 (m, 1H), 3.75 - 3.63 (m, 2H), 3.26 - 3.22 (m, 1H), 2.89 - 2.78 (m, 3H), 2.74 - 2.61 (m, 3H), 2.10 - 2.00 (m, 3H), 1.95 (d, J = 6.6 Hz, 3H), 1.82 - 1.70 (m, 2H). HRMS (ESI) calcd for C₃₇H₃₆Cl₂FN₈O₆ [M+ H]⁺: 777.2113; found, 777.1842.

Compound Example 155: synthesis of 4-((4-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151081)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151019) was used to prepare SIAIS151081 (yellow solid, 26.3 mg, 75%). ¹H NMR (500 MHz, MeOD) δ 7.88 (d, J = 2.8 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J = 1.4 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.31 - 7.25 (m, 1H), 7.14 (d, J = 1.3 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.02 - 6.94 (m, 1H), 6.34 (q, J = 6.6 Hz, 1H), 5.07 - 4.99 (m, 1H), 4.64 (d, J = 13.5 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.08 (d, J = 13.5 Hz, 1H), 3.42 (t, J = 6.7 Hz, 2H), 3.25 (t, J = 13.0 Hz, 1H), 2.87 - 2.80 (m, 2H), 2.75 - 2.65 (m, 2H), 2.62 - 2.57 (d, J = 7.1 Hz, 1H), 2.56 - 2.50 (m, 1H), 2.16 - 2.04 (m, 3H), 2.03 - 1.96 (m, 2H), 1.95 (d, J = 6.6 Hz, 3H), 1.87 - 1.77 (m, 2H). HRMS (ESI) calcd for C₃₈H₃₈Cl₂FN₈O₆ [M+ H]⁺: 791.2270; found, 791.1991.

Compound Example 156: synthesis of 4-((5-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151082)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151020) was used to prepare SIAIS151082 (yellow solid, 25.0 mg, 70%). ¹H NMR (500 MHz, MeOD) δ 7.91 (s, 1H), 7.64 - 7.62 (m, 2H), 7.59 (m, 1H), 7.55 - 7.49 (m, 2H), 7.28 (t, J = 8.6 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.37 - 6.32 (m, 1H), 5.06 - 4.95 (m, 1H), 4.63 (d, J = 14.0 Hz, 1H), 4.48 - 4.42 (m, 1H), 4.08 (d, J = 13.3 Hz, 1H), 3.41 - 3.35 (m, 2H), 3.30 - 3.24 (m, 1H), 2.88 - 2.76 (m, 2H), 2.75 - 2.62 (m, 2H), 2.55 - 2.48 (m, 2H), 2.17 - 2.03 (m, 3H), 1.95 (d, J = 6.6 Hz, 3H), 1.91 - 1.78 (m, 2H), 1.77 - 1.68 (m, 4H). HRMS (ESI) calcd for C₃₉H₄₀Cl₂FN₈O₆ [M+ H]⁺: 805.2426; found 805.2123.

Compound Example 157: synthesis of 4-((6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS151085)

According to the procedures for the preparation of Compound Example 1, Crizotinib and intermediate LM (SIAIS151027) was used to prepare SIAIS151085 (yellow solid, 19.5 mg, 54%). ¹H NMR (500 MHz, MeOD) δ 7.91 (s, 1H), 7.63 (s, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.53 - 7.49 (m, 2H), 7.28 (t, J = 8.6 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.99 (dd, J = 7.1, 1.8 Hz, 1H), 6.36 - 6.31 (m, 1H), 5.04 - 5.00 (m, 1H), 4.64 (d, J = 13.5 Hz, 1H), 4.48 - 4.42 (m, 1H), 4.10 (d, J = 13.7 Hz, 1H), 3.35 (t, J = 6.8 Hz, 2H), 3.30 - 3.23 (m, 1H), 2.87 - 2.78 (m, 2H), 2.75 - 2.65 (m, 2H), 2.53 - 2.43 (m, 2H), 2.21 - 2.05 (m, 3H), 1.95 (d, J = 6.7 Hz, 3H), 1.93 - 1.79 (m, 2H), 1.74 - 1.66 (m, 4H), 1.54 - 1.47 (m, 2H). HRMS (ESI) calcd for C₄₀H₄₂Cl₂FN₈O₆ [M+ H]⁺: 819.2583; found 819.2583.

Compound Example 158: synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylbutanamide. (SIAIS220030)

Step 1: Synthesis of tert-butyl (1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)(methyl) carbamate (SIAIS220025) according to scheme 16:

SIAIS151054 (1 g, 2.85 mmol) and anhydrous tetrahydrofuran (15 mL) were added to a three-necked flask, the mixture was evacuated and replaced with nitrogen three times, then NaH (60% in oil, 342 mg, 8.55 mmol) was added in portions under ice-water bath, the resulting mixture was stirred under ice-water bath for 1 h, then methyl iodide (2g, 8.55 mmol) was slowly added dropwise to the reaction system and the solution was stirred at room temperation for 5 h. When the reaction was complete, water was added slowly under ice-water bath to quench the reaction, the resulting solution was extracted with ethyl acetate, washed with water, brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a yellow oil (SIAIS220025) , the crude was used for the following reaction without further purification. (1000 mg, 96%) ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J = 9.4 Hz, 1H), 6.42 (dd, J = 9.4, 2.5 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H), 4.38 - 4.20 (m, 1H), 3.98 (d, J = 13.0 Hz, 2H), 3.94 (s, 3H), 3.01 (t, J = 12.0 Hz, 2H), 2.72 (s, 3H), 1.80 - 1.72 (m, 4H), 1.47 (s, 9H). HRMS (ESI) calcd for C₁₈H₂₈N₃O₅ ⁺[M+H]⁺, 366.2023; found, 366.2019.

Step 2: Synthesis of tert-butyl (1-(4-amino-3-methoxyphenyl)piperidin-4-yl)(methyl) carbamate (SIAIS220028) according to scheme 16:

SIAIS220025 (900 mg, 2.46 mmol), ethanol (15 mL) and water (15 mL) were added to a egg-shaped flask, followed by ammonium chloride (520 mg, 9.84 mmol) and iron powder (700 mg, 12.30 mmol), then the resulting mixture was slowly heated to reflux for 2 h. When the reaction was complete, the crude mixture was concentrated under reduced pressue, extracted with DCM (3 x 50 mL), the combined organic layer was washed with water and brine (20 mL), then dried over anhydrous Na₂SO₄ and concentrated in vacuum to afford SIAIS220028 in 85% yield (700 mg) as a white solid. The crude was used for the following reaction without further purification. ¹H NMR (500 MHz, CDCl₃) δ 6.63 (d, J = 8.3 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 8.3, 2.4 Hz, 1H), 3.83 (s, 3H), 3.56-3.50 (m, 3H), 2.77 (s, 3H), 2.70 (t, J = 11.5 Hz, 2H), 1.91 - 1.83 (m, 2H), 1.75 - 1.70 (m, 2H), 1.47 (s, 9H). HRMS (ESI) calcd for C₁₈H₃₀N₃O₃ ⁺ [M+H]⁺, 336.2282; found, 336.2286.

Step 3: Synthesis of tert-butyl (1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)Piperidin-4-yl)(methyl) carbamate (SIAIS220029A) according to scheme 16:

To a solution of 2,5-dichloro-N-(2-(dimethylphosphoryl)phenyl)pyrimidin-4-amine (405 mg, 1.28 mmol) in anhydrous DMF (10 mL) were added SIAIS220028 (410 mg, 1.22 mmol), Pd(OAc)₂ (29 mg, 0.13 mmol), Xantphos (64 mg, 0.13 mmol) and Cs₂CO₃(1.26 g, 3.84 mmol) in a 100 mL egg-shaped flask, the solution was purged and refilled with argon three times. Then the mixture was slowly heated to 110°C and stirred for 7 h. After the starting material was consumed, the reaction mixture was filtered through a pad of silica gel, then extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na₂SO₄. The solvent was evaporated under the reduced pressure and the residue was purified by silica gel chromatography (eluent: MeOH/DCM = 3:97) to give the title compound (300 mg, 38%) as a brown solid. ¹H NMR (500 MHz, CDCl₃) δ 10.80 (s, 1H), 8.62 (dd, J = 8.4, 4.4 Hz, 1H), 8.09 (d, J = 9.5 Hz, 2H), 7.49 (t, J = 7.9 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.12 (dd, J = 10.4, 4.3 Hz, 1H), 6.56 (d, J = 2.1 Hz, 1H), 6.50 (dd, J = 8.8, 2.3 Hz, 1H), 4.30 - 4.10 (m, 1H), 3.88 (d, J = 8.4 Hz, 3H), 3.65 (d, J = 12.2 Hz, 2H), 2.78 (s, 3H), 2.84 - 2.72 (m, 2H), 1.93 - 1.86 (m, 2H), 1.85 (s, 3H), 1.82 (s, 3H), 1.79 - 1.73 (m, 2H), 1.48 (s, 9H). HRMS (ESI) calcd for C₃₀H₄₁ClN₆O₄P⁺ [M+H]⁺, 615.2610; found, 615.2606.

Step 4: Synthesis of SIAIS220029B according to scheme 16:

To a solution of SIAIS220029A (250 mg, 0.40 mmol) in DCM (6 mL) was added TFA (2 mL) at room temperature, the resulting solution was stirred at room temperature for 1 h. When the reaction was complete detected by LC-MS, most of the solvent was removed under the reduced pressure, 10 mL 10% MeOH/ DCM was added, the pH of the solution was adjusted to 8-9 with saturated NaHCO₃ solution, then extracted with DCM, dried over anhydrous Na₂SO₄. The solvent was evaporated under the reduced pressure to afford SIAIS220029B. The crude was used for the following reaction without further purification.

Step 5: Synthesis of N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylbutanamide (SIAIS220030) according to scheme 16:

SIAIS220029B (15 mg, 0.029 mmol, 1 equiv), SIAIS151019 (10.4 mg, 0.029 mmol, 1 equiv)), HATU (22.1 mg, 0.058 mmol, 2 equiv), DIPEA (18.7 mg, 0.145 mmol, 5 equiv) and anhydrous DMF (2 mL) were added sequentially in a 25 mL flask at RT. The resulting reaction mixture was stirred at room temperature overnight. After the reaction was complete detected by LC-MS, the reaction solution was purified by preparative HPLC, eluent (v/v) : acetonitrile/(water+0.5%HCl) = 10% -100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS220030 was obtained as yellow solid (10.2 mg, 76%). ¹H NMR (500 MHz, MeOD) δ 8.34 (s, 1H), 8.06 (s, 1H), 7.69 - 7.60 (m, 2H), 7.56 (dt, J = 8.4, 6.5 Hz, 2H), 7.31 (dd, J = 15.9, 8.0 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.04 (dd, J = 7.0, 4.4 Hz, 1H), 6.84 - 6.48 (m, 2H), 5.05 (dd, J = 12.6, 5.5 Hz, 1H), 4.95 (dd, J = 12.5, 5.5 Hz, 1H), 3.87 (s, 3H), 3.87 - 3.61 (m, 3H), 3.46 - 3.40 (m, 2H), 2.94 (s, 2H), 2.85 - 2.81 (m, 2H), 2.76 - 2.70 (m, 2H), 2.64 - 2.58 (m, 2H), 2.53 (t, J = 6.9 Hz, 1H), 2.17 - 2.05 (m, 1H), 2.03 - 1.95 (m, 4H), 1.87 (d, J = 2.5 Hz, 3H), 1.84 (d, J = 2.5 Hz, 3H), 1.76 - 1.70 (m, 2H). HRMS (ESI) calcd for C₄₂H₄₈ClN₉O₇P⁺ [M+H]⁺, 856.3097; found, 856.3095.

Compound Example 159: synthesis of 4-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS220026)

Step 1: Synthesis of (2-((2-((4-(4-((4-aminobutyl)amino)piperidin-1-yl)-2-methoxyphenyl) amino)-5-chloropyrimidine-4-yl)amino)phenyl)dimethylphosphine oxide (SIAIS220022) according to scheme 17:

SIAIS151101 (100 mg, 0.20 mmol),tert-butyl (4-bromobutyl) carbamate (76 mg, 0.30 mmol), DIPEA (129 mg, 1.00 mmol) and NMP (3 mL) were added sequentially in a 50 mL egg-shaped flask at RT. The resulting reaction mixture was slowly heated to 90 °C under an atmosphere of nitrogen and then stirred for 2 h. After the reaction was complete detected by LC-MS, the reaction solution was purified by reverse phase chromatography, eluent (v/v) : acetonitrile/(water+0.5%HCl) = 10% -100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS220022 was obtained as a brown solid (30 mg, 22%). ¹H NMR (500 MHz, MeOD) δ 8.32 (dd, J = 8.0, 4.4 Hz, 1H), 8.03 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 14.0, 6.4 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.27 (t, J = 6.9 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.45 (dd, J = 8.8, 2.5 Hz, 1H), 3.85 (s, 3H), 3.75 - 3.72 (m, 2H), 3.22 - 3.11 (m, 1H), 3.05 (dd, J = 17.3, 10.1 Hz, 2H), 2.99 (t, J = 6.7 Hz, 2H), 2.78 (t, J = 11.5 Hz, 2H), 2.20 (d, J = 11.3 Hz, 2H), 1.85 (s, 3H), 1.82 (s, 3H), 1.82 - 1.71 (m, 6H). HRMS (ESI) calcd for C₂₈H₄₀ClN₇O₂P⁺ [M+H]⁺, 572.2664; found, 572.2660.

Step 2: Synthesis of 4-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl) isoindolin-1,3-dione (SIAIS220026) according to scheme 17:

SIAIS220022 (25 mg, 0.04 mmol),2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (11 mg, 0.04 mmol), DIPEA (26 mg, 0.20 mmol) and NMP (1 mL) were added sequentially in a 25 mL egg-shaped flask at RT. The resulting reaction mixture was slowly heated to 110 °C under an atmosphere of nitrogen and then stirred for 1 h. After the reaction was complete detected by LC-MS, the reaction solution was purified by reverse phase chromatography, eluent (v/v): acetonitrile/(water+0.5%HCl) = 10% -100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS220026 was obtained as a yellow solid (2.3 mg, 17%). ¹H NMR (500 MHz, MeOD) δ 8.35 - 8.33 (m, 1H), 8.06 (s, 1H), 7.88 - 8.86 (m, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.57 - 7.45 (m, 2H), 7.28 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 2.3 Hz, 1H), 6.47 (d, J = 8.5 Hz, 1H), 5.14 - 5.12 (m, 1H), 3.86 (s, 3H), 3.75 - 3.72 (m, 3H), 3.19 - 2.99 (m, 3H), 2.90 - 2.85 (m, 1H), 2.79 - 2.73 (m, 2H), 2.53 - 2.45 (m, 2H), 2.30 - 2.13 (m, 6H), 1.87 - 1.76 (m, 10H). HRMS (ESI) calcd for C₄₁H₄₈ClN₉O₆P⁺ [M+H] ⁺ , 828.3148; found, 828.3143.

Compound Example 160: synthesis of 4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. (SIAIS220027) Synthesis of Brigatinib Analogue D (SIAIS220023)

Brigatinib Analogue D was synthesized according to scheme 1, using similar procedures for the preparation of Brigatinib Analogue A in Intermediate Example 1.
(2-((2-((4-(4-(4-(4-(2-aminoethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (SIAIS220023), yellow solid, 30 mg, 27% yield. ¹H NMR (500 MHz, MeOD) δ 8.33 (dd, J = 8.2, 4.5 Hz, 1H), 8.04 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.65 - 7.60 (m, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.28 (t, J = 6.9 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.7, 2.4 Hz, 1H), 3.88 - 3.80 (m, 2H), 3.65 (s, 3H), 3.65 - 3.61 (m, 1H), 3.36 - 3.30 (m, 8H), 3.12 - 3.08 (m, 2H), 2.81 (t, J = 11.7 Hz, 2H), 2.77 - 2.72 (m, 2H), 2.28 (d, J = 12.4 Hz, 2H), 1.95 - 1.89 (m, 2H), 1.85 (s, 3H), 1.83 (s, 3H). HRMS (ESI) calcd for C₃₀H₄₃ClN₈O₂P⁺ [M+H]⁺: 613.2930, found 613.2925.

Synthesis of the title compound SIAIS220027:

According to step 2 of the preparation of Compound Example 159, Brigatinib Analogue D (SIAIS220023) instead of SIAIS220022 was used to prepare SIAIS220027 (yellow solid, 3.1 mg, 23%).¹H NMR (500 MHz, MeOD) δ 8.33 (dd, J = 8.3, 4.5 Hz, 1H), 8.04 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 6.7 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 6.69 (d, J = 2.4 Hz, 1H), 6.46 (dd, J = 8.7, 2.4 Hz, 1H), 5.34 (t, J = 4.8 Hz, 1H), 5.07 (dd, J = 12.6, 5.6 Hz, 1H), 4.60 - 4.56 (m, 4H), 3.86 (s, 3H), 3.79 (d, J = 12.0 Hz, 2H), 3.64 (s, 1H), 2.88 - 2.86 (m, 1H), 2.77 - 2.75 (m, 2H), 2.21 - 2.17 (m, 4H), 2.16 - 2.10 (m, 1H), 1.85 (s, 3H), 1.82 (s, 3H), 1.63 - 1.57 (m, 2H), 1.40 - 1.36 (m, 2H). HRMS (ESI) calcd for C₄₃H₅₁ClN₁₀O₆P⁺ [M+H]⁺: 869.3414, found 869.3414.

Comparative Example 161: synthesis of 4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (SIAIS1210003)

Step 1: Synthesis of 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (SIAIS1213161) according to scheme 18:

2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (2 g, 7.24 mmol), Potassium carbonate (2 g, 14.48 mmol) and DMF (8 mL) were added sequentially in a 50 mL egg-shaped flask at RT, then methyl iodide (2 g, 14.48 mmol) was slowly added dropwise to the reaction system under an atmosphere of nitrogen and the solution was slowly heated to 60 °C and stirred for 4 h. When the reaction was complete detected by LC-MS, the reaction solution was purified by reverse phase chromatography, eluent (v/v): acetonitrile/(water+0.5%HCl) = 10% -100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS1213161 was obtained as a gray solid (736 mg, 35%).¹H NMR (500 MHz, DMSO) δ 7.97-7.93 (m, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.74 (t, J = 8.9 Hz, 1H), 5.22 (dd, J = 13.1, 5.4 Hz, 1H), 3.02 (s, 3H), 2.99-2.92 (m, 1H), 2.80-2.75 (m, 1H), 2.58 - 2.52 (m, 1H), 2.11-2.05 (m, 1H). HRMS (ESI) calcd for C₁₄H₁₂FN₂O₄ ⁺ [M+H] ⁺, 291.0776; found, 291.0771.

Step 2: Synthesis of (2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl) aminoacetic acid (SIAIS1213171) according to scheme 18:

SIAIS1213161 (500 mg, 1.72 mmol),tert-butyl aminoacetate (339 mg, 2.59 mmol), DIPEA (668 mg, 5.17 mmol) and NMP (5 mL) were added sequentially in a 50 mL egg-shaped flask at RT. The resulting reaction mixture was slowly heated to 110 °C under an atmosphere of nitrogen and then stirred for 3 h. After the reaction was complete detected by LC-MS, the reaction solution was purified by reverse phase chromatography, eluent (v/v): acetonitrile/(water+0.5%HCl) = 10% -100%, after concentration under reduced pressure and freeze-drying, the desired tert-butyl ester intermediate was obtained. This intermediate was added to a 25 mL flask, followed by DCM (5 mL) and TFA (2 mL), then stirred at room temperature for 1 h. After concentration under reduced pressure and freeze-drying, the desired product SIAIS1213171 was obtained as yellow solid (421 mg, 71% yield). ¹H NMR (500 MHz, MeOD) δ 7.58 (dd, J = 8.5, 7.2 Hz, 1H), 7.11 (d, J = 7.0 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 5.10 (dd, J = 12.9, 5.5 Hz, 1H), 4.13 (s, 2H), 3.15 (s, 3H), 2.88 (d, J = 4.0 Hz, 2H), 2.73 - 2.65 (m, 1H), 2.14 - 2.06 (m, 1H). HRMS (ESI) calcd for C₁₆H₁₆N₃O₆ ⁺ [M+H] ⁺, 346.1034; found, 346.1030.

Step 3: Synthesis of 4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (SIAIS1210003) according to scheme 18:

Brigatinib Analogue C SIAIS164005 (15 mg, 0.026 mmol, 1 equiv), SIAIS1213171 (9 mg, 0.026 mmol, 1 equiv) ), HOAT (7.1 mg, 0.052 mmol, 2 equiv), EDCI (10 mg, 0.052 mmol, 2 equiv) DMF (2 mL) and NMM (15.2 mg, 0.15 mmol, 5 equiv) were added sequentially in a reaction bottle at RT. The resulting reaction mixture was stirred at room temperature overnight. After the reaction was complete detected by LC-MS, the reaction solution was purified by preparative HPLC, eluent (v/v) : acetonitrile/(water+0.5%HCl) = 10% -100%, after concentration under reduced pressure and freeze-drying, the desired product SIAIS1210003 was obtained as yellow solid (8.8 mg, 43%).¹H NMR (500 MHz, MeOD) δ 8.41 (s, 1H), 8.09 (d, J = 17.8 Hz, 1H), 7.69 (dd, J = 14.1, 7.7 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 12.5, 5.5 Hz, 1H), 4.28 (s, 2H), 3.99 (d, J = 12.4 Hz, 2H), 3.88 (s, 3H), 3.71 - 3.34 (m, 9H), 3.16 (s, 3H), 2.99 - 2.82 (m, 3H), 2.79 - 2.70 (m, 2H), 2.29 (d, J = 11.4 Hz, 2H), 2.19 - 2.08 (m, 1H), 2.03 - 1.94 (m, 2H), 1.89 (d, J = 13.6 Hz, 6H). HRMS (ESI) calcd for C₄₄H₅₁ClN₁₀O₇P⁺ [M+H] ⁺, 897.3363; found, 897.2919.

Bioactivity assay

Biological Materials

Halt proteinase and phosphatase inhibitor (Thermo Fisher)
Cell TITER BLUE detection kit (Promega)
Cell TITER GLO detection kit (Promega)
RPMI1640 and serum from (Gibico company)
Cell Counting Kit-8 (CCK-8 ,WST) reagent (Dojindo)
Fetal Bovine Serum (FBS) (Gibico)
Penicillin-Streptomycin (Gibico)
SuperSignal West Pico Chemiluminescent Substrate (Thermo Fisher)
SuperSignal West Femto Maximum Sensitivity Substrate (Thermo Fisher)
Cycloheximide (Sigma)

Antibodies: antibodies of ALK (#3633S) and p-ALK (#6962S), AKT(#4691S), p-AKT (#4060S), p-ERK (#4370) and ERK(#9107S) were purchased from Cell Signaling Technology, Tunulin and GAPDH antibody were purchased from Abcam.

Cell culture

ALK gene rearrangement-positive cell lines used included: H2228 (EML4-ALK V3, non-small cell lung cancer), H3122 (EML4-ALK V1, non-small cell lung cancer) and SR cells (NPM-ALK, human anaplastic large cell lymphoma (ALCL)). EGFR mutant cell lines included PC9 (EGFR exon 19 deletion mutation, non-small cell lung cancer), PC9Brc1 (EGFR exon 19 deletion mutation T790M, non-small cell lung cancer) and SW48 (EGFR mutation, colorectal cancer). SR (NPM-ALK) and NCI-H2228 (EML4-ALK, V3) cells were purchased from ATCC. Human brain glioblastoma U118MG cells were purchased from ATCC and acute myeloid leukemia cells MOLM13 were tested in Shanghai ChemPartner. NCI-H3122 (EML4-ALK, V1) cells were from NCI (Bethesda, MD, see ref: Fujishita et al., 2003). PC9 (EGFR, exon 19 del) and PC9Brc1 (EGFR, exon 19 del T790M) were got as previous and as a gift of Katerin Politi (Xiaoling Song et al., 2015). All Cells were cultured in RPMI1640 medium with 10% FBS and Penicillin-Streptomycin in 37 °C incubator with 5% CO₂. All cell lines were maintained in active growing state without reaching confluence, and all cell lines were STR idenitified and examined as mycoplasma free by regular check.

Western blot

Cancer cells were seeded in 1 ml RPMI1640 medium in 12-well plate at the density of 1.5 x 10^5 cells/ml. The next day cells were treated with different concentration of testing drugs for 16 hours. Then cells were washed with PBS and placed on ice and lyzed in RIPA lysis buffer with Halt Proteinase and Phosphotase inhibitor. The lysate was centrifuged at 10000RPM at 4°C for 10 mins and the supernatant was collected. Equal amount of proteins were added to 4XSDS loading solution and denatured at 95°C for 5 minutes, then frozen to -20°C or directly loaded to run SDS-PAGE gels after denature. The electrophoresis gel was a protein precast gel (4-20%) purchased from Genscript. The electrophoresis tank and related components were purchased from Bio-rad. The electrophoresis was carried out at a constant voltage of 120V for 2 hours. The electro-transfer was performed on ice at a constant 400mA current for 1h. The gels were blotted to PVDF membrane. After transfer, the membrane was blocked with 5% milk in TBST for half an hour. Detailed procedures of immunoblotting were referred to the Antibody Manual of Cell Signaling Technology.
DC₅₀ (concentration required to degrade protein by half) were calculated based on the intensity from western blot, and data were analyzed via Prism GraphPad with non-linear regression.

Evaluation of compounds IC50s

The IC₅₀ values of the compounds of the present disclosure were measured using Cell Titer Blue and Cell Titer GLO reagents from Promega Corporation or commercial WST reagents. Cells were seeded in 100 microliters RPMI medium containing serum at specific density of 2000 cells/well one day before treatment. Cells were treated with a series concentration of different compounds and the parental drugs and incubated for 72 hours. Viable cells were measured via the above cell viability detection reagents. Cells in the negative control (DMSO) and the positive control (the parental drug) were treated in the same manner as the compound of the present disclosure. IC50s were calculated via Prism Graphad. Experiments were repeated at least three times. Results were summarized in Tables 3-12.

Colony formation assay

Cells were digested to become single cell suspension and counted. Cells were seeded in the intensity of 250 cells/well in 12 well plate. Treated cells at the concentration of 100, 250, 500 nM. Fixed cells 2-3 weeks after and stained cells with crystyl violate.

Results:

The PROTAD molecules developed in the present disclosure were based on ALK tyrosine kinase inhibitors, which can be chosen from Criztinib, Ceritinib, Alectinib, Brigatinib, TAE684, ASP3026, GSK1838795A, AZD3463, Entrectinib(RXDX-101) and Ensartinib (X-396) etc. Deffierent ALK inhibitors-based ALK PROTAD molecules can degrade ALK proteins, and inhibit the phosphorylation of ALK protein and the proliferation of ALK mutant positive cells. These ALK PROTAD molecules can be developed into new therapeutic ways to treat cancer patients.

I. Bioactivity assay for Brigatinib-based PROTAD molecule

Brigatinib-based PROTAD molecules of the present disclosure can degrade ALK proteins, and inhibit the phosphorylation of ALK protein and the proliferation of ALK mutant positive tumor cells.

1. 1 Effect of Brigatinib based PROTAD molecules on the growth inhibition on ALK mutant positive tumor cells

We performed dose-dependent effect test for these compounds in SR cells, which contain NPM-ALK gene fusion and highly sensitive to ALK inhibitors. SR cells were treated with different concentration of PROTAD molecules (started from 10uM, 3 or 5 folds dilution for 10 concentrations) for 72 hours, CCK8(WST) reagent was then used to examinate cell number to determine the IC50s. Experiments were repeated for more than 3 times, results were summarized in Table 3.
Resutls showed that Brigatinib based PROTAD molecules can effectively inhibit the growth of SR cells (Table 3). The IC50 of the parental drug Brigatinib in SR cells was 2.8 nM. The PROTAD compounds we developed kept about similar growth inhibition effect as Brigatinib. Some of the PROTAD compounds of the present invention had significant lower IC50 in killing SR cells as compared with the parental drugs. For example, the IC50 of compound SIAIS1197055 in SR cells was about 1 nM.

Besides above, we also tested the dosage-dependent effects on the growth inhibition in H2228 cells. The compounds we developed also showed growth inhibition on H2228 cells. (Table 3).

Table 3. The IC50 of Brigatinib-based PROTAD molecules in ALCL and lung adenocarcinoma cell lines.

Cell line	PROTAD compounds	Test reagen	IC₅₀ (nM)
SR	Brigatinib	WST	2.8±0.4
SR	Brigatinib Analogue A (SIAIS1197135)	WST	1.6±1.0
SR	SIAIS 1197065	WST	20.7±14.9
SR	SIAIS 1197067	WST	16.1±6.1
SR	SIAIS 1197069	WST	22.3±18.2
SR	SIAIS 1197073	WST	34.2±23.9
SR	SIAIS1197055	WST	1.0±0.7
SR	SIAIS1197057	WST	17.7±9.6
SR	SIAIS 1197059	WST	10.7±6.2
SR	SIAIS 1197061	WST	8.0±4.4
SR	SIAIS 1197063	WST	14.1±7.3
SR	SIAIS 1197077	WST	7.9±4.9
SR	SIAIS 1197087	WST	10.6±2.4
SR	SIAIS197079	WST	15.9±8.5
SR	SIAIS1197081	WST	32.5±19.8
SR	SIAIS 1197083	WST	49.9±30.8
SR	SIAIS 1197085	WST	62.5±39.2
SR	SIAIS1197145	WST	8.5±5.6
SR	SIAIS1197147	WST	14.2±8.2
SR	SIAIS1197149	WST	8.2±3.9
SR	SIAIS1197151	WST	16.7±7.3
SR	SIAIS1197153	WST	4.6±1.9
SR	SIAIS1197155	WST	3.4±0.5
SR	SIAIS1197157	WST	3.1±1.3
SR	Brigatinib Analogue B(SIAIS 151101)	WST	1.7±1.4
SR	SIAIS151113	WST	7.5±5.2
SR	SIAIS151114	WST	10.9±7.5
SR	SIAIS151115	WST	8.0±3.2
SR	SIAIS151116	WST	15.3±9.8
SR	SIAIS 151117	WST	30.9±21.3
SR	SIAIS151120	WST	11.4±7.8
SR	SIAIS151121	WST	20.4±8.5
SR	SIAIS151118	WST	0.9±0.2
SR	SIAIS151119	WST	1.6±1.0
SR	SIAIS151123	WST	1.9±1.5
SR	SIAIS219151	WST	102.3±4.8
SR	SIAIS219128	WST	6.67±1
SR	SIAIS219152	WST	3.78±0.4
SR	SIAIS219153	WST	3.12±0.2
SR	SIAIS219154	WST	3.8±0.2
SR	SIAIS219170	WST	10.8±1.4
SR	SIAIS220030	WST	5.8
SR	SIAIS220026	WST	7.4
SR	SIAIS164157	WST	15.7±15.0
SR	SIAIS151124	WST	76.9±15.9
SR	SIAIS151128	WST	6.3±0.2
SR	SIAIS151125	WST	61.9±30.5
SR	SIAIS151126	WST	31.9±11.9
SR	SIAIS151127	WST	36.4±23.5
SR	SIAIS 164143	WST	11.7±4.2
SR	SIAIS164144	WST	13.6±9.1
SR	SIAIS 164145	WST	10.3±6.3
SR	SIAIS 164146	WST	3.6±2.1
SR	SIAIS164147	WST	2.0±1.2
SR	SIAIS 164148	WST	1.5±0.8
SR	SIAIS 164149	WST	2.3±2.0
SR	SIAIS1210117	WST	1.7±1.0
SR	Brigatinib Analogue C(SIAIS 164005)	WST	6.7±3.1
SR	SIAIS 164007	WST	3.8±1.9
SR	SIAIS 164008	WST	3.6±2.1
SR	SIAIS 164009	WST	5.3±1.7
SR	SIAIS164016	WST	11.2±6.8
SR	SIAIS164017	WST	14.0±8.6
SR	SIAIS164018	WST	2.0±1.4
SR	SIAIS164019	WST	9.6±8.0
SR	SIAIS 164020	WST	2.9±1.5
SR	SIAIS 164021	WST	7.4±5.0
SR	SIAIS 164022	WST	3.3±2.2
SR	SIAIS 164023	WST	4.8±2.7
SR	SIAIS219073	WST	1.8±1
SR	SIAIS219155	WST	4.34±0.4
SR	SIAIS219156	WST	3.09±0.2
SR	SIAIS219157	WST	1.99±0.2
SR	SIAIS219124	WST	2.47±0.6
SR	SIAIS219158	WST	30.3±3.8
SR	SIAIS220027	WST	3.8
SR	SIAIS 164152	WST	7.9±3.5
SR	SIAIS 164041	WST	42.7±29.4
SR	SIAIS164032	WST	54.5±31.2
SR	SIAIS164033	WST	50.1±34.9
SR	SIAIS164034	WST	88.6±63.0
SR	SIAIS164035	WST	41.8±24.7
SR	SIAIS164120	WST	19.2±8.8
SR	SIAIS164121	WST	21.6±12.5
SR	SIAIS164122	WST	12.1±9.2
SR	SIAIS164123	WST	11.4±8.1
SR	SIAIS164124	WST	9.5±8.1
SR	SIAIS164125	WST	9.0±5.7
SR	SIAIS164126	WST	8.0±6.7
SR	SIAIS 164153	WST	55.9±19.9
H2228	Brigatinib	WST	45.2
H2228	SIAIS151118	WST	346.3
H2228	SIAIS1210117	WST	30.3
H2228	SIAIS 164008	WST	74.0
H2228	SIAIS164018	WST	17.9
H2228	SIAIS 164023	WST	15.5

1.2 Effect of Brigatinib based ALK PROTADS on the level of ALK Protein

The effect of Brigtinib based PROTAD molecules on the ALK protein total level were studied by western blot in ALCL SR (NPM-ALK) cell line and lung adenocarcinoma cell line H2228(EML4-ALK) and H3122 (EML4-ALK). The results were shown in Figures 1-6 and table 6. SR cells were treated with Brigatinib at different concentrations (0, 10, 50, 100, 500 nM) for 16 hours. The cell lysate was used to measure the effect of Brigtinib on ALK protein level by Western blotting (Figure 1 and Table 6). Results indicated that Brigatinib did not degrade ALK proteins (Figure 1).
The effects of Brigatinib Analogue A-based PROTAD compounds on ALK protein level were shown in Figs 1-2 and Table 6. With the increase of concentration, more ALK proteins were degraded in lung cancer H3122 cells. In the meanwhile, the phosphorylation of ALK protein was also significantly inhibited (Figrue 2).
Results showed Brigatinib Analogue B based PROTADs molecules not only significantly induced ALK protein degradation (Figs. 3-4 and table 6), but also significantly reduced the phosphorylation of ALK protein (Figs. 4-5). Besides that, the down-stream signaling pathway such as PI3K/AKT pathway was also significantly inhibited.
The results for the effect of Brigatinib Analogue C based PROTADs molecules on ALK protein degradations were shown in Fig. 6 and table 6. In SR cell line, parental drug Brigatinib Analogue C (SIAIS 164005) did not degrade ALK protein even at the concentration of 500 nM. However, Brigatinib Analogue C based PROTAD compounds effectively degrade ALK proteins. PROTAD compound SIAIS 164018 degraded ALK proteins at the concentration less than 1 nM in SR cells, and a similar effects was observed in H3122 cells (Figure 7 and table 6). Other PROTAD compounds also showed the abilities to degrade ALK protein at the concentration lower than 10 nM. For example, compound SIAIS 164009, SIAIS 164021 and SIAIS 164153 degraded ALK proteins at the concentration of 1 nM. These results indicated that the PROTADs molecules we developed had good protein degradation capabilities. Besides that, the compounds we developed also significantly inhibited the phosphorylation of ALK protein (Figrue 7).
The effects of compounds SIAIS 164008 and SIAIS 164018 of the present invention on the activation of ALK mediated signaling pathways were also studied in SR cells and H2228 cells (Fig. 8). Both of these two compounds effectively degrade ALK proteins. In SR cells, both compounds inhibited the phophorylation of ALK proteins at the concentration of 0.1nM and downstream signaling pathway such as PI3K/AKT, MEK/ERK and STAT3 pathway were all significantly inhibited. Both SIAIS 164008 and SIAIS 164018 also inhibited the phosphorylation of ALK protein and activation of PI3K/AKT pathway as well in lung cancer cell line H2228 cells although H2228 cells were less sensitive than SR cells. The overall effect of compound of SIAIS 164018 was better than that of SIAIS 164008.
In summary, we successfully developed Brigatinib based PROTAD compopunds. These PROTAD compopunds reduced ALK protein levels, blocked ALK down-stream signaling, inhibited the growth of cancer cells, and potentially could be used in cancer therapy.

II. Bioactivity assay for Alectinib based ALK PROTAD

Alectinib (Roche) was approve on Nov 7, 2017 by FDA to treat ALK mutant positive metastic non-small cell lung cancer. Three different Alectinib analogues (A, B, and C) were designed and generated, and these three different forms of Alectinib analogues were used to develop ALK PROTADs compounds. The IC50s of these Alectinib based ALK PROTADs compounds were tested in SR cells and the results were listed in table 4. The IC50 of Alectinib in SR cells was 10.6 nM. Within these different Alectinib Analogue forms, the growth inhibition effect of Alectinib Analogue A is better than that of Alectinib, while the effect of Alectinib Analogue B and C were slightly weaker than that of Alectinib in inhibiting the growth of SR cells. Even with the addition of different E3 linkers, the developed ALK PROTAD compounds retained the growth inhibition in SR cells.

Table 4. The IC50s of Alectinib based ALK PROTAD compopunds

Cell line	Compounds' name	Testing reagents	IC₅₀ (nM)
SR	Alectinib	WST	10.6
SR	Alectinib Analogue A	WST	2.4
SR	SIAIS164012	WST	48.9
SR	SIAIS164014	WST	81.0
SR	SIAIS164028	WST	19.7
SR	SIAIS164024	WST	35.8
SR	SIAIS164026	WST	147.9
SR	SIAIS164036	WST	131.9
SR	SIAIS164094	WST	124.0
SR	SIAIS164095	WST	71.3
SR	SIAIS164096	WST	79.5
SR	SIAIS164155	WST	103.7
SR	SIAIS164029	WST	27.3
SR	SIAIS164037	WST	152.8
SR	Alectinib Analogue B(SIAIS184193)	WST	14.7
SR	SIAIS219023	WST	29.3
SR	SIAIS219024	WST	73.1
SR	SIAIS219001	WST	21.3
SR	SIAIS219010	WST	31.1
SR	SIAIS219011	WST	49.9
SR	SIAIS219020	WST	30.3
SR	SIAIS219021	WST	115
SR	Alectinib Analogue C(SIAIS184192)	WST	19.1
SR	SIAIS219018	WST	13.3
SR	SIAIS219019	WST	38.3
SR	SIAIS184194	WST	24.2
SR	SIAIS219003	WST	21.8
SR	SIAIS219004	WST	36.8
SR	SIAIS219015	WST	110.3
SR	SIAIS219016	WST	80.8

The effect of Alectinib-based ALK PROTAD compounds on ALK protein level and down-stream signaling pathway were studied in ALCL cell line SR and non-small cell lung cancer cell line H3122 (Figures 9 and 10). Alectinib did not degrade ALK proteins at the concentration of 1-500 nM in SR cell. However, Alectinib Analogue A-based ALK PROTAD compounds could degrade ALK proteins in these cells (Figure 9 and table 6). In addition, Alectinib based ALK PROTAD compounds also could degrade ALK protein in H3122 lung cancer cells.
The phosphorylation of ALK protein is an indication of ALK activation. The study compared the effects of the compounds of the present invention on ALK phosphorylation. After ALK mutant cells H3122 were treated with various concentrations of Alectinib and Alectinib based compounds for 24 hours, protein samples were collected and detected by Western blotting for the total amount of ALK protein and phosphorylation. In H3122 cell line, Alectinib inhibited the phosphorylation of ALK but not affected the total protein level of ALK (Figure 10). In contrast, Alectinib based ALK PROTAD compounds exhibited different degradation capabilities on ALK protein (Figure 10 and Table 6). These ALK PROTAD compounds also inhibited the phosphorylation of ALK protein. These results indicated that Alectinib based-ALK PROTAD compounds not only retained the capabilities to inhibit ALK phosphorylation but also able to degrade ALK proteins, which fully showed the advantage of ALK PROTAD compounds comparing to ALK kinase inhibitors.
Accordingly, Alectinib based ALK PROTAD compounds also blocked the activation of ALK downstream signaling. The effect of parental compound Alectinib on the phosphorylation of AKT protein is not obvious, and the effect of Alectinib on the ERK phosphorylation increased slightly at a concentration of 50-100 nM. Alectinib based ALK PROTAD compounds such as SIAIS 164024 and SIAIS 164026 not only reduced the protein level of ALK protein at a concentration lower than InM, but also inhibited the phosphorylation of AKT and ERK.
In summary, Alectinib based ALK PROTAD compounds not only effectively reduced ALK protein level, but also reduced the phosphorylation of AKT and ERK and affected ALK-mediated signaling pathway.

III. Bioactivities assay of Ceritinib and Crizotinib based ALK PROTAD comppounds

Our data indicated that Certinib-based ALK PROTAD comppounds also not only degraded ALK protein, inhibited ALK kinase activities, but also inhibited the growth of ALK mutant positive cells. In the meanwhile, Crizotinib based ALK PROTAD compounds also could reduce the level of ALK protein.

3.1 Both Ceritinib and Crizotinib-based ALK PROTAD compounds effectively reduced ALK protein level

H3122 cells were seeded at 3x10⁶ cells per well one day before treatment. Cells were treated with a series concentration of different compounds, and DMSO was used as the control. After 24 hours, protein samples were collected to detect the total level of ALK protein. Results showed that, Ceritnib did not affect ALK protein level in H3122 cells even at the concentration as high as 500 nM (Figure 11). However, Ceritinib based-ALK PROTAD compounds could induce significant reduction of ALK protein level in the dose-dependent manner (Figure 11 and Table 6). For example, ALK PROTAD compound SIAIS074024 reduced ALK protein level at the concentration as low as 50 nM.
Similarly, Crizotinib-based ALK PROTAD compound SIAIS151082 could also reduce ALK protein level at the concentration of lower than 50 nM (Figure 12 and Table 6).

3.2 The effect on cell growth for Certinib-based ALK PROTAD compounds

The effect of Certinib-based ALK PROTAD compounds on ALK mutant positive cells were examined in H3122 cells. H3122 cells were seeded at a density of 2000 cells per well. After treated with testing compounds for 72h, cells were assayed for viability by using Cell Titer Glo or using specific testing reagents as indicated in the table 5. The cell growth curve was drawn with Graphpad. Results were summarized in Table 5. The Certinib-based ALK PROTAD compounds can inhibit the growth of ALK mutant positive tumor cells (table 5). Certain ALK PROTAD compounds such as SIAIS074008 and SIAIS074032 had a very potent growth inhibition effect (IC50 at the nano mole range) in SR and H3122 cells (Table 5), and SIAIS074017 showed a growth inhibitory effect comparable to the parental drug.

Table 5. The IC50s for Ceritinib based ALK PROTAD compounds

Cell line	Compounds' name	Testing reagents	IC₅₀ (µM)
SR	Ceritinib	WST	0.016
SR	SIAIS151031	WST	0.085
SR	SIAIS151028	WST	0.038
SR	SIAIS074017	WST	0.116
H3122	Ceritinib	CTB	0.014
H3122	SIAIS074017	CTB	0.045
H3122	SIAIS074018	CTB	0.209
H3122	SIAIS074021	CTB	0.125
H3122	SIAIS074022	CTB	0.269
H3122	SIAIS074008	CTB	0.428
H3122	SIAIS074024	CTB	0.721
H3122	SIAIS074025	CTB	1.241
H3122	SIAIS074026	CTB	2.560
H3122	SIAIS074036	CTB	3.900
H3122	SIAIS151023	CTB	0.015
H3122	SIAIS151028	CTB	0.006
H3122	SIAIS151029	CTB	0.023
H3122	SIAIS151031	CTB	0.007
H3122	SIAIS151034	CTB	0.014
H3122	SIAIS151035	CTB	0.033
H3122	SIAIS151036	CTB	0.031
H3122	SIAIS151037	CTB	0.151
H3122	SIAIS151038	CTB	0.393
H3122	SIAIS151039	CTB	0.441
H3122	SIAIS151040	CTB	0.141
H3122	SIAIS151041	CTB	0.332
H3122	SIAIS151042	CTB	0.153
H3122	SIAIS151043	CTB	0.156
H3122	Ceritinib	CTG	0.044
H3122	SIAIS074017	CTG	0.041
H3122	SIAIS151023	CTG	0.076
H3122	SIAIS151028	CTG	0.080
H3122	SIAIS151029	CTG	0.095
H3122	SIAIS151031	CTG	0.081
H3122	DMSO	CTB	17.19

CTB: Cell Titer Blue;
CTG: Cell Titer Glo.

Summary from above, the bioactivities of different ALK PROTAD compounds were evaluated in ALCL SR cell lines and non-small cell line H3122 cells. Resulted showed these ALK PROTAD compounds could effectively reduce ALK protein level in SR and H3122 cell lines (Table 6). These compounds could inhibit ALK kinase activities, block ALK-dependent downstream signalin pathway, and finally inhibit the growth of ALK mutant positive tumor cells.

Table 6. The DC50s of ALK PROTAD compounds in SR and H3122 cells

ALK PROTAD Compounds	DC₅₀ (nM) in SR	DC₅₀ (nM) ) in H3122
Brigtinib	not degrade	nt
Brigatinib Analogue A SIAIS1197053	not degrade	nt
SIAIS1197065	nt	100-500
SIAIS1197067	nt	100-500
SIAIS1197069	nt	100-500
SIAIS1197073	nt	100-500
SIAIS1197055	1-10	1-50
SIAIS1197057	nt	50-500
SIAIS1197059	nt	1-50
SIAIS1197061	nt	50-500
SIAIS1197063	nt	50-500
SIAIS1197077	0.1-0.5	50-500
SIAIS164156	nt	50-500
SIAIS1197087	nt	50-500
SIAIS197079	nt	50-500
SIAIS1197081	nt	50-500
SIAIS1197083	nt	50-500
SIAIS1197085	nt	20-100
SIAIS1197145	nt	1-50
SIAIS1197147	nt	20-100
SIAIS1197149	nt	20-100
SIAIS1197151	nt	20-100
SIAIS1197153	1-50	1-50
SIAIS1197155	1-10	1-50
SIAIS1197157	1-10	1-50
Brigatinib Analogue B SIAIS151101	Not degrade	Not degrade
SIAIS151113	nt	100-500
SIAIS151114	nt	100-500
SIAIS151115	nt	100-500
SIAIS151116	nt	100-500
SIAIS151120	nt	20-100
SIAIS151121	nt	100-500
SIAIS151118	1-10	1-50
SIAIS151119	nt	100-500
SIAIS151123	0.1-2	1-50
SIAIS164157	nt	1-50
SIAIS151124	nt	100-500
SIAIS151128	nt	100-500
SIAIS151125	nt	100-500
SIAIS151126	nt	100-500
SIAIS151127	nt	20-100
SIAIS164143	1-10	50-100
SIAIS164144	1-10	20-100
SIAIS164145	1-10	50-100
SIAIS164146	1-10	0.1-10
SIAIS164147	1-10	0.02-1
SIAIS164148	1-10	1-50
SIAIS164149	1-10	0.02-20
SIAIS1210117	0.5-10	nt
Brigatinib Analogue C SIAIS164005	Not degrade	Not degrade
SIAIS164007	1-10	10-50
SIAIS164008	1-10	10-50
SIAIS164009	1-10	1-10
SIAIS164016	1-10	1-10
SIAIS164017	100-500	0.02-20
SIAIS164018	0.5-1	1-10
SIAIS164019	1-10	10-20
SIAIS164020	0.5-10	1-50
SIAIS164021	0.1-0.5	1-10
SIAIS164022	1-10	1-10
SIAIS164023	0.5-10	1-10
SIAIS164152	0.5-10	10-50
SIAIS164041	10-50	10-500
SIAIS164032	100-500	20-100
SIAIS164033	100-500	100-500
SIAIS164034	100-500	100-500
SIAIS164035	100-500	100-500
SIAIS164120	1-10	10-100
SIAIS164121	1-10	50-100
SIAIS164122	1-50	50-100
SIAIS164123	1-50	10-50
SIAIS164124	1-10	100-500
SIAIS164125	1-10	10-50
SIAIS164126	1-10	10-50
SIAIS164153	100-500	1-10
Alectinib	Not degrade	>500
Alectinib Analogue A	nt	nt
SIAIS164011	nt	nt
SIAIS164012	1-50	1-50
SIAIS164014	nt	100-500
SIAIS164028	1-50	1-10
SIAIS164029	nt	nt
SIAIS164024	nt	1-10
SIAIS164026	nt	1-10
SIAIS164036	nt	20-100
SIAIS164094	nt	20-100
SIAIS164095	nt	nt
SIAIS164096	nt	nt
SIAIS164155	nt	10-50
Ceritnib	nt	Not degrade
SIAIS074017	nt	100-500
SIAIS074018	nt	100-500
SIAIS074021	nt	50-100
SIAIS074022	nt	20-100
SIAIS074024	nt	10-50
SIAIS074025	nt	100-500
SIAIS151023	nt	10-100
SIAIS151029	nt	10-50
SIAIS151037	nt	50-100
SIAIS151035	nt	50-100
SIAIS151031	nt	100-500
SIAIS151028	nt	20-100
SIAIS151032	nt	20-100
Crizotinib	nt	100-500
SIAIS151060	nt	100-500
SIAIS151082	nt	1-10
SIAIS151083	nt	10-50

nt: not tested

IV. The effect of ALK PROTAD compounds on ALK resistance mutation

Drug resistance always occurs after treating ALK mutant positive lung cancer patients with ALK inhibitor drugs. The resistance mechanisms include acquiring resistant mutations in ALK protein such as gate keeper mutation L1196M and C1156Y. We tested the growth inhibition effect with Brigatinib-based ALK PROTAD compounds developed in this present invention in mutant ALK expressing Ba/F3 cells, and the results were summarized in table 7. Results showed that ALK PROTAD compounds not only inhibited the growth of EML4-ALK that was wild type in the ALK kinase domain, but also inhibited the growth of EML4-ALK that harbored L1196M and C1156Y mutant mutations in the kinase domain.

Table 7: The IC50s of Brigatinib based ALK PROTAD compounds against ALK resistant mutations

Cell line	Compounds	IC₅₀ (nM)
Ba/F3 (EML4-ALK/WT)	Crizotinib	188.6
	Brigatinib	11
	SIAIS164008	114.6
	SIAIS164018	30.9
	SIAIS164023	33.6
	SIAIS164142	64.7
	SIAIS1210117	123.4
	SIAIS151118	92
Ba/F3 (EML4-ALK/L1196M)	Crizotinib	395
	Brigatinib	35.9
	SIAIS164008	376.2
	SIAIS164018	57.4
	SIAIS164023	75.8
	SIAIS164142	117
	SIAIS1210117	170.4
	SIAIS151118	145.8
Ba/F3 (EML4-ALK/C1156Y)	Crizotinib	366.8
	Brigatinib	36.8
	SIAIS164008	242.5
	SIAIS164018	42.7
	SIAIS164023	47.5
	SIAIS164142	92.1
	SIAIS1210117	119.5
	SIAIS151118	128.9

V. The mechanisms study for ALK PROTAD compounds in cells

5.1 ALK PROTAD compounds reduced the stability of ALK proteins

The mechanism of PROTAD compounds to degrade their target proteins act through recruiting E3 ubiquitining ligase to the proximity of the target protein, which leads to the target protein being highly ubiquitinzed and eventually being degraded. In order to study the acting mechanisms of ALK PROTAD compounds that we developed, we firstly examined the half-life of ALK protein. Because the total level of ALK protein was determined by both the translational activitiy and protein degradation, we used cyclohexmide to stop protein translation to examine the effect of ALK PROTAD compounds on ALK protein stabilities.
Here we took the data for Ceritinib-based ALK PROTAD compounds as an example on protein stability. Data for other ALK PROTAD compounds were tested in the same way and similar results were found. H3122 cells were firstly treated with 0.5 µM Ceritinib and Certinib based ALK PROTAD compounds for 24 hours, and 1µg/ml cyclohexmide was used to stop protein translation. The difference at the total ALK protein level would reflect the different influence of drugs on protein stability. Results showed ALK protein level did not show much changes after 12 hours of Ceritinib treatment (Figures 11 & 13). However, ALK PROTAD compound SIAIS074017 significantly reduced ALK protein level even as early as after 7 hours of-treatment. This indicated that the ALK PROTAD compounds treatment promoted the degradation of ALK protein.

5.2 ALK PROTAD compounds act through the proteosome to perform their function

In order to study the time- and dose- dependent effect of ALK PROTAD compounds to ALK proteins, we firstly examined the effect of Brigatinib on ALK protein level (Fig. 14). ALCL cell line SR was treated with Brigatinib at a serial concentration of Brigatinib from 30 nM to 300 µM for 4-24 hours.Western blot was used to examine the level of ALK protein. Results showed with different concentration of Brigatinib did not affect ALK protein levels.
We also tested the effects of an ALK PROTAD compound SIAIS1210117 on ALK protein levels within a time course. Results showed at the concentration of 100nM, treating SR cells with SIAIS1210117 for 4 hours could lead to significant ALK protein degradation (Figure 15). To further confirm the degradation act through E3 ubiqutinase, an inactive epimer of SIAIS 1210117 was synthesized as a control compound, i.e., SIAIS219050, which was similar to SIAIS1210117 in the structure except it lost the ability of recruiting E3-ligase. An inactive epimer of SIAIS164018, i.e., SIAIS1210003 was also synthesized as a control compound. Results showed that this epimer SIAIS219050 did not induce degradation of ALK protein even after 24 hours treatment.
To further validate the degradation effect act through proteasome mediated pathway, we also treated cells with two different proteosome inhibitors MG132 and MLN4924 to block protein degradation (Figure 16). Results showed that although SIAIS1210117 reduced ALK protein level in SR cells, and this effect was able to be blocked by proteosome inhibitor MG132 and MLN4924. Whereas the control epimer SIAIS219050 did not have such effect. The same results were observed for ALK PROTAD compound SIAIS164018. The degradation of ALK protein by SIAIS164018 was able to be blocked by MK132 and MLN4924, and there was no such effect on the negative epimer SIAIS1210003 of SIAIS164018. This further indicated that the ALK PROTAD compounds act through the proteosome degradation pathway.

VI. The effect of ALK PROTAD compounds on the colony formation ability of cancer cells

In order to see the effect of ALK PROTAD compounds on the colony formation ability of cancer cells, EML4-ALK mutant lung cancer cells H2228 were firstly seeded in 12 well plate at the density of 200 cells per well one day before treatment. Cells were treated with different ALK PROTAD compounds at different concentration. ALK PROTAD compounds SIAIS1210117, SIAIS164018 and their epimers were used as an example, and results were shown in Figure 17. Both negative control epimers could not inhibit the colony formation of H2228 cells, and two ALK PROTAD compounds SIAIS1210117 and SIAIS164018 dramatically inhibited the colony formation of H2228 cells.

VII. The effect of ALK PROTAD compounds on EGFR mutant cells

7.1 ALK PROTAD compounds inhibited the growth of EGFR mutant cells

Previous results showed that Brigatinib could inhibit the activity of EGFR. So we tested the effect of ALK PROTAD compounds on two different EGFR mutant lung cancer cell lines. PC9 cells contain EGFR exon19 deletion mutation and PC9Brc1 cells harbor exon 19 deletion and a T790M point mutation. Results showed ALK PROTAD compounds also could inhibit the growth of EGFR mutant non-small cell lung cancer cells even for PC9Brc1 cells that carry with resistant mutations against EGFR TKIs (Tables 8-9).

Table 8. The IC50s of ALK PROTAD compounds in lung adenocarcinoma PC9 cells

(n ≥ 3)	Half Inhibitory Concentration (IC₅₀)
(n ≥ 3)	Mean (nM)	Standard Error	Testing Reagent
Brigatinib	102	33	CTB
SIAIS164007	358	35	CTB
SIAIS164008	265	28	CTB
SIAIS164018	150	36	CTB
SIAIS164021	434	178	CTB
SIAIS164022	233	91	CTB
SIAIS164023	379	92	CTB
SIAIS164147	321	74	CTB
SIAIS164148	153	44	CTB
SIAIS164149	187	26	CTB
SIAIS1210117	106	26	CTB

Table 9. The IC50s of ALK PROTAD compounds in lung cancer cell line PC9Brc1

(n ≥ 3)	Half Inhibitory Concentration (IC₅₀)
(n ≥ 3)	Mean (nM)	Standard Error (SE)	Testing Reagent
Brigatinib	246	31	CTB
SIAIS164007	1606	194	CTB
SIAIS164008	1834	430	CTB
SIAIS164018	900	166	CTB
SIAIS164021	2445	1062	CTB
SIAIS164022	696	428	CTB
SIAIS164023	870	289	CTB
SIAIS164147	1285	158	CTB
SIAIS164148	1340	139	CTB
SIAIS164149	988	116	CTB
SIAIS1210117	460	66	CTB

7.2. The effect of ALK PROTAD compounds on the colny formation of EGFR mutant cells

ALK PROTOAD compounds we developed also could significantly inhibit the colony formation ability of EGFR mutant non-small cell lung cancer. Results were shown in Figure 18 and Figure 19.

7.3. The growth inhibition effect of ALK PROTAD compounds on EGFR mutant colorectal cancer cell line SW48

Colorectal cancer cell line SW48 harbors an EGFR G719S mutation. We tested ALK PROTAD compounds we developed in this cell line, and we found our ALK PROTAD compounds had better growth inhibition effect than Brigatinib (see Table 10 and Figure 20).

Table 10. The IC50s of ALK PROTAD compounds in SW48 cell line

(n=2)	Half Inhibitory Concentration (IC₅₀)
(n=2)	Mean (µM)	Standard Error (SE)	Reagent
Crizotinib	0.19	0.03	CTG
Alectinib	0.80	0.22	CTG
Brigatinib	2.72	0.70	CTG
SIAIS164008	15.25	1.68	CTG
SIAIS164018	2.76	0.12	CTG
SIAIS219073	>20	Na	CTG
SIAIS1210117	1.36	0.01	CTG
SIAIS151118	1.92	0.07	CTG

na: not available

VIII. The effect of ALK PROTAD compounds on ROS1 mutant cells

Human glioblastoma cell line U118MG carries a FIG-ROS1 gene fusion. We have treated U118MG cells with ALK PROTAD compounds at a serial concentration for 72 hours and the IC50s were summarized in Table 11. Results showed that different ALK inhibitor drugs had different cell killing potency in this ROS1 mutant cell line, and ALK PROTAD compounds showed better activity than their parental drug Brigatinib in the ability to inhibit cell growth. The IC50 for Brigatinib in U118MG cells was about 6.8µM, and Brigatinib based ALK PROTAD compound SIAIS1210117 had an IC50 about 0.92µM (Table 11).

Table 11. The IC50s of ALK PROTAD compounds in glioblastoma cell line U118MG

(n=2)	Half Inhibitory Concentration (IC₅₀)
(n=2)	Mean (µM)	Standard Error (SE)	Reagent
Crizotinib	2.57	0.39	CTG
Alectinib	1.48	0.29	CTG
Brigatinib	6.80	2.00	CTG
SIAIS164008	3.52	3.17	CTG
SIAIS164018	16.88	14.38	CTG
SIAIS219073	>20	na	CTG
SIAIS1210117	0.92	0.09	CTG
SIAIS151118	4.26	0.25	CTG

na: not available

IX. The effect of ALK PROTAD compounds on FLT3 mutant cancer cells

We also tested the effect of ALK PROTAD compounds in FLT3 mutant cell line. MOLM13 is an acute monocytic leukemia cell line with mutation of FLT3-ITD mutation. Parental drug Brigatinib inhibited MOLM13 cells with an IC50 about 152 nM (Table 12). Selelcted ALK PROTAD compound SIAIS164018 and SIAIS151118 both showed a better growth inhibition effect than Brigatinib with an IC50 value of 79 nM and 101 nM respectively.

Table 12. The IC50s of ALK PROTAD compounds in AML cell line MOLM13

(n=2)	Half Inhibitory Concentration (IC₅₀)
(n=2)	Mean (µM)	Standard Error (SE)	Reagent
Crizotinib	291	69	CTG
Alectinib	255	35	CTG
Brigatinib	152	14	CTG
SIAIS164008	392	10	CTG
SIAIS164018	79	18	CTG
SIAIS219073	373	68	CTG
SIAIS1210117	345	10	CTG
SIAIS151118	101	9	CTG

X. The pharmacokinetics (PK) study of ALK PROTAD compounds

SD rat were used to study the PK of ALK PROTAD compounds. ALK PROTAD compounds SIAIS164008, SIAIS164018, SIAIS164023 and SIAIS 151118 were administrated into SD rat via three different routes: .IV (Intravenous Injection), IP (Intraperitoneal Injection) and PO (paricalcitol to oral). Blood smples at different sampling time points up to 24 hours post dosing were collected from each animal and analyzed with LC-MS/MS to calculate the PK for each chemical.
Results showed that, after administering to SD rats via IV at a single dose of 2 mg/kg ALK PROTAD compounds (SIAIS 164008, SIAIS164018, SIAIS164023 and SIAIS151118), testing ALK PROTAD compounds were quickly distributed in blood, with the maximal peak levels were reached about at 0.083-2 hours, and serum clearance half-life was about 0.85, 4.65, 7,71, and 4.73 hours, and the mean value of clearance rates were about 414.27, 22.63, 88.16, and 6.35 mL/min/kg. When administrated ALK PROTAD compounds via IP at the dose of 2 mg/kg, the time to maximal serum peak level (Tmax) were about 0.42, 2.67, 2.00, and 1.67 hours for these compounds respectively, and the serum half-life were 1.54, 3.65, 1.62, and 3.27 hours respectively, and the bioavailability were 92.96%, 157.49%, 122.13%, and224.67%, respectively. When administrated these ALK PROTAD compounds via PO at the dose of 10 mg/kg, the Tmax were 2.75, 2.00, 3.33, and 3.33 hours respectively, and the serum half-life were 3.98, 7.09, 2.13 and 4.66 hours, and the bioavailable were 14.89%, 18.38%, 34.43%, and 35.99% respectively.
In summary, ALK PROTAD compounds we developed could promote the degradation of ALK protein, inhibit the phosphorylation of ALK , block ALK-mediated signaling pathway, inhibit the proliferation and reduce the colony formation abilities in ALK mutant positive cancer cells. In the meanwhile, ALK PROTAD compounds also could inhibit the growth of cancer cells harboring EGFR activating mutations, FLT3 activating mutation and ROS1 gene rearrangement with a lower IC50 value comparing to parental drug. These developed ALK PROTAD compounds also had a good PK in rat. These compounds had a long serum half-life, good oral bioavailabilities, and are suitable for therapeutic treatment of human cancer.

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Claims

A compound of formula (I)
or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof, in which:
ALK-TKI is covalently connected to LIN via group A, and ULM is covalently connected to LIN;

wherein ALK-TKI is an ALK tyrosine kinase inhibitor or an analogue thereof with the same function;

LIN is a linking group, which represents a linear or branched alkylene chain, a spiro-cycloalkylene, a 1,4-piperazinylene, or a 1,3-dialkynylene group, wherein the linear or branched alkylene chain is optionally interrupted one or more times by one or more selected from the group consisting of O, C(O)NH, NHC(O), NHC(O)NH, NH, S, sulfinyl, sulfonyl, aminosulfonylamino, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, or heteroarylene group, or any combination thereof, wherein the linear or branched alkylene chain is optionally substituted with one or more substituents;

ULM is a small molecule ligand of VHL or CRBN protease with ubiquitination function; and

the group A is C(O) or absent.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, wherein the ALK-TKI is the structure represented by the following general formula:

wherein, R represents an alkyl group or H.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 2, wherein R represents a linear or branched C_1-10 alkyl group.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to any one of claims 1-3, wherein the ULM represents the structure of the following formula (II):
wherein X represents CH₂ or C(O), Y represents CH₂, NH or O, and Z represents a carbonyl group or is absent.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to any one of claims 1-3, wherein the ULM represents the structure of the following formula (III):

wherein Z represents a carbonyl group or is absent.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to any one of claims 1 to 5, wherein the LIN represents: linear or branched C_1-20 alkylene chain; -(CH₂)_n1-(O(CH₂)_n2)_m1-; -(CH₂)_n1-(O(CH₂)_n2)_m1-O-(CH₂)_n3-; -(CR₁R₂)_n1-(O(CR₁R₂)_n2)_m1-O-(CR₁R₂)_n3-; -(CH₂)_n1-(C(O)NH-(CH₂)_n2)_m1-; -(CH₂)_n1-(C(O)NH-(CH₂)_n2)_m1-(CH₂)_n3-; -(CH₂)_n1-(O(CH₂)_n2)_n1-O-(CH₂)_n3-C(O)NH-(CH₂)_n4-(O(CH₂)_n5)_m2-O-(CH₂)_n6-; - (CR₁R₂)_n1-(O(CR₁R₂)_n2)_m1-O-(CR₁R₂)_n3-C(O)NH-(CR₁R₂)_n4-(O(CR₁R₂)_n5)_m2-O-(CR₁R₂)_n6-; - (CH₂)_n1-C(O)NH-(O(CR₁R₂)_n2)_m1-; linear or branched alkylene chain interrupted one or more times by one or more selected from the group consisting of NHC(O), NHC(O)NH, S, sulfinyl, sulfonyl, alkynylene, alkenylene, cycloalkylene, arylene , heterocyclylene, heteroarylene, or any combination thereof; or -(CH₂)_n1-(O(CH₂)_n2)_m1- in which alkylene carbon chain is interrupted one or more times by one or more selected from the group consisting of arylene, heterocyclylene, heteroarylene or any combination thereof;
wherein R₁ and R₂ each independently represent a linear or branched C_1-10 alkyl group or a cycloalkyl group; and
n1, n2, n3, n4, n5, n6, m1, and m2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN represents:
-(CH₂)₂O(CH₂)₂OCH₂-; -CH₂O(CH₂)₂OCH₂-; -(CH₂)₃O(CH₂)₂-; -(CH₂)₃O(CH₂)₂O(CH₂)₂-; - (CH₂)₃O(CH₂)₃-; -(CH₂)₂O(CH₂)₂-; -(CH₂)₂O(CH₂)₂O(CH₂)₂-; -(CH₂)₂O(CH₂)₂O(CH₂)₂-; -(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂-; -(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₃-; -(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂-; -(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂-; -(CH₂)₃O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂-; or -(CH₂)₃O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₂O(CH₂)₃-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN represents: -CH₂-; -(CH₂)₂-; -(CH₂)₃-; -(CH₂)₄-; - (CH₂)₅-; -(CH₂)₆-; -(CH₂)₇-; -(CH₂)₈-; -(CH₂)₉-; -(CH₂)₁₀-; -(CH₂)₁₁-; -(CH₂)₁₂-; -(CH₂)₁₃-; - (CH₂)₁₄-; -(CH₂)₁₅-; -(CH₂)₁₆-; -(CH₂)₁₇-; -(CH₂)₁₈-; -(CH₂)₁₉-; or -(CH₂)₂₀-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, wherein the substituent for the linear or branched alkylene chain is selected from the group consisting of hydroxyl, amino, mercapto, halogen, or any combination thereof.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 9, wherein the LIN represents a linear or branched C_1-20alkylene chain substituted with one or more substituent groups selected from the group consisting of hydroxyl, amino, mercapto, halogen, or any combination thereof.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 9, wherein the LIN represents -(CH₂)₃CH(OH)CH(OH)(CH₂)₄-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to any one of claims 1 to 5, wherein the LIN represents: -(CH₂)_n1-triazolylene-(CH₂)_n2-, -(CH₂)_n1-(O(CH₂)_n2)_m1-O-(CH₂)_n3-triazolylene-(CH₂)_n4-(O(CH₂)_n5)_m2-O-(CH₂)_n6-, - (CH₂)_n1-triazolylene-(CH₂)_n2-(O(CH₂)_n3)_m1-O-(CH₂)_n4-, or -(CH₂)_n1-(O(CH₂)_n2)_m1-O-(CH₂)_n3-triazolylene-(CH₂)_n4-; and
n1, n2, n3, n4, n5, n6, m1, and m2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 12, wherein the LIN represents:
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN represents:
-(CH₂)₂C(O)NH(CH₂)₂-; -(CH₂)₃C(O)NH(CH₂)₃-; -(CH₂)₃C(O)NH(CH₂)₄-; - (CH₂)₆C(O)NH(CH₂)₇-; or -(CH₂)₈C(O)NH(CH₂)₈-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is -(CH₂)_n1-NHC(O)-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 15, wherein the LIN is -(CH₂)₃NHC(O)(CH₂)₃-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is -(CH₂)_n1-NHC(O)NH-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 17, wherein the LIN is -(CH₂)₄NHC(O)NH(CH₂)₄-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is -(CH₂)_n1-S-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 19, wherein the LIN is -(CH₂)₅S(CH₂)₅- or -(CH₂)₆S(CH₂)₅-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is -(CH₂)_n1-S(O)-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 21, wherein the LIN is -(CH₂)₅S(O)(CH₂)₅- or -(CH₂)₆S(O)(CH₂)₅-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is -(CH₂)_n1-S(O)₂-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 23, wherein the LIN is -(CH₂)₅S(O)₂(CH₂)₅- or -(CH₂)₆S(O)₂(CH₂)₅-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is -(CH₂)_n1-CH=CH-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 25, wherein the LIN is -(CH₂)₄CH=CH(CH₂)₃-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is -(CH₂)_n1-C≡C-(CH₂)_n2- or -(CH₂)_n1-C≡C-C≡C-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 27, wherein the LIN is - (CH₂)₂C≡C(CH₂)₂- or - (CH₂)₅C≡C(CH₂)₄-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 6, wherein the LIN is a linear or branched alkylene chain interrupted one or more times by one or more selected from the group consisting of NHC(O), NHC(O)NH, S, sulfinyl, sulfonyl, alkynylene, alkenylene, spiro-cycloalkylene, arylene, heterocyclylene, heteroarylene group, or any combination thereof.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 29, wherein the LIN is -(CH₂)_n1-piperazinylene-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 30, wherein the LIN is: -CH₂-piperazinylene-CH₂-, -(CH₂)₂-piperazinylene-(CH₂)₂-, -(CH₂)₃-piperazinylene-(CH₂)₃-, -(CH₂)₂-piperazinylene-(CH₂)₃-, -CH₂-piperazinylene-(CH₂)₂-, -CH₂-piperazinylene-(CH₂)₃-, or -(CH₂)₂-piperazinylene-(CH₂)₃-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 29, wherein the LIN is -(CH₂)_n1-phenylene-(CH₂)_n2-, wherein n1 and n2 each independently represent an interger of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 32, wherein the LIN is: -CH₂-phenylene-CH₂-, -(CH₂)₂-phenylene-(CH₂)₂-, -CH₂-phenylene-(CH₂)₂-, -(CH₂)₂-phenylene-CH₂-, -(CH₂)₃-phenylene-(CH₂)₃-, -CH₂-phenylene-(CH₂)₃-, -(CH₂)₂-phenylene-(CH₂)₃-, -(CH₂)₃-phenylene-(CH₂)₂-, or -(CH₂)₃-phenylene-CH₂-.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to any one of claims 1 to 5, wherein the LIN represents 1,4-piperazinylene, spiro-cycloalkylene or 1,3-dialkynylene group.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 34, wherein the LIN represents:
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 35, wherein the LIN represents:
and the group A is C(O).
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, which is selected from the group consisting of:
4-((2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-(2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((2-(2-(2-(3-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((15-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((18-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-(19-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,7,10,13,16-pentaoxanonadecyl)-1 -oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((5-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3 -yl)-1,3 -dioxoisoindolin-4-yl)-7-oxoheptanamide;

7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-7-oxoheptanamide;

4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)heptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)heptyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)heptanamide;

4-((5-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)sulfinyl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((5-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)sulfonyl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((12-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-12-oxododec-5-yn-1-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy) propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)propoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(8-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(9-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-l-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(10-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

N1-(4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutyl)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)propanamide;

4-((2-(2-(2-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)propoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((2-(2-(2-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)propoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)ethoxy)ethoxy)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-amide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-amide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)heptanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)heptanamide;

4-((7-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)heptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptanamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)heptanediamide;

(2S,4R)-1-((S)-2-(2-(2-(2-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N16-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13-tetraoxahexadecanediamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N19-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13,16-pentaoxanonadecanediamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)succinamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)adipamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N7-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)heptanediamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)octanediamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N9-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)nonanediamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)succinamide;

4-((2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-(2-(2-(3-(4-(l-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((2-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-l-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((15-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((18-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-(5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(8-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(9-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(10-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-4-oxobutanamide;

(2S,4R)-1-((S)-2-(4-(4-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

8-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamide;

8-(4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihy dro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexanamide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl))piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanamide;

8-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)heptanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-((1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)amino)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(5-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(6-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(7-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(8-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(9-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N9-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)nonanediamide;

(2S,4R)-1-((S)-2-(9-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(10-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-4-oxobutanamide;

(2S,4R)-1-((S)-2-(4-(4-(4-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(4-(4-(4-((1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)amino)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(4-(4-(4-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

4-((2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)propoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-(2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-(3-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-(2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)propoxy)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((2-(2-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((18-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-18-oxo-3,6,912,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-(4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-6-oxohexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1 -yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carbonyl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-((4-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-4-oxobutyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(6-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(7-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(9-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(10-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(11-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino-yl)-11-oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(5-(5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentanamido)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

4-((2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(3-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propoxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((2-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(2-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione;

4-((15-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((18-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((4-(4-(4-(6-amino-5-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((5-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(9-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-9-oxononyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-(9-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-9-oxononyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-8-oxooctanamide;

4-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)octyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)octyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((12-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-12-oxododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((16-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-16-oxohexadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)-8-oxooctanamide;

4-((5-(4-(6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)-1H-1,2,3-triazol-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((5-((6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)thio)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((5-((6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)sulfinyl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((5-((6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)sulfonyl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

1-(5-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-oxopentyl)-3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)urea;

4-(((E)-10-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-10-oxodec-4-en-1-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((10-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5,6-dihydroxy-10-oxodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((7-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-7-oxohept-3-yn-1-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

(2S,4R)-1-((S)-2-(4-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(6-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-((8-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)octyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(10-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-(4-(5-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-oxopentanamido)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-16-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tert-butyl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-19-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tert-butyl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-22-(4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tert-butyl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(6-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(6-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-l-yl)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

4-((8-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((8-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((2-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

(2S,4R)-4-hydroxy-1-((S)-2-(13-(4-(1-(5-isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-2-methylphenyl)piperidin-4-yl)piperazin-l-yl)-13-oxotridecanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

2-(2,6-dioxopiperidin-3-yl)-4-((12-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3, 5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-12-oxododecyl)amino)isoindoline-1,3-dione;

3-(4-((12-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-12-oxododecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-12-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-12-oxododecanamide;

2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-(3-(4-(l-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione;

N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N13-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyltridecanediamide;

(2S,4R)-1-((S)-2-(tert-butyl)-19-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-17-methyl-4,16,19-trioxo-7,10,13-trioxa-3,17-diazanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

2-((2-((1-(N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

2-((2-((1-(N-(8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

N1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N8-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N8-methyloctanediamide;

2-((2-((1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-13-methyl-12-oxo-3,6,9-trioxa-13-azapentadecan-15-oyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyladipamide;

(2S,4R)-1-((S)-2-(6-((1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)(methyl)amino)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-17-(tert-butyl)-2-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3,15-dioxo-6,9,12-trioxa-2,16-diazaoctadecan-18-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methyldodecanamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-12-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-N-methyldodecanamide;

N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N12-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N1-methyldodecanediamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide;

(2S,4R)-1-((S)-2-(13-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-13-oxotridecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(13-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)tridecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-l-((S)-2-(tert-butyl)-16-(4-(4-((5-(3,5-difluorobenzyl)-lH-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3R,5S)-4-(13-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-13-oxotridecyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3R,5S)-4-((S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azaheptadecyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3R,5S)-4-(13-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-13-oxotridecanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3R,5S)-4-((S)-3-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,2-dimethyl-5-oxo-7,11,14-trioxa-4-azaheptadecan-17-oyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)decanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)decyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; and

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide.
The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to claim 1, which is selected from the group consisting of:
3-(4-((2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((2-(2-(2-(3-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((15-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((18-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((2-(2-(3-(4-( 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)propoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-(2-(2-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((5-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-5-oxopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((6-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((2-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((7-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-(3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-3-oxopropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-amide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-amide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)acetamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylbutanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-N-methylbutanamide;

4-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)butyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)(methyl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propanamide;

N-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanamide;

N1-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N11-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)undecanediamide;

(2S,4R)-1-((S)-2-(8-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-((8-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)octyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(11-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-((11-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-11-oxoundecyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-((11-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)undecyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(4-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-3-oxopropyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(4-(3-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-3-oxopropyl)phenyl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

3-(4-((2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((2-(2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((15-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((18-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)ethoxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

(2S,4R)-1-((S)-2-(3-(4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)phenyl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

3-(4-((2-(4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-((4-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)phenethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

8-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)glycyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

(2S,4R)-1-((S)-2-(8-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanamide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-amide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-amide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanamide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanamide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)acetamide;

N-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanamide;

(2S,4R)-1-((S)-2-(2-(2-(2-((1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)amino)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-((1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)amino)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N16-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13-tetraoxahexadecanediamide;

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N19-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13,16-pentaoxanonadecanediamide;

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)succinamide;

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide;

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)adipamide;

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N7-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)heptanediamide;

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)octanediamide;

N1-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamide;

8-(4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(1-((2-(2,6-dioxopiperidm-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dim ethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(4-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(5-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(6-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(7-(4-(1-(3-cyano-9-ethyl-6,6-dim ethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(8-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(10-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

4-((2-(3-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(2-(3-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3 -yl)isoindoline-1,3 -dione;

4-((18-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((2-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((3-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((4-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((5-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((6-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

4-((7-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-((2-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1 -yl)-4,19-dioxo-7,10,13,16-tetraoxa-3 -azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(4-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-3,3 - dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(5-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(7-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(8-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(9-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(10-(4-(1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

2-(2,6-dioxopiperidin-3-yl)-4-((2-(3-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)isoindoline-1,3-dione;

2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione;

2-(2,6-dioxopiperidin-3-yl)-4-((15-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)isoindoline-1,3-dione;

2-(2,6-dioxopiperidin-3-yl)-4-((18-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)isoindoline-1,3-dione;

2-(2,6-dioxopiperidin-3-yl)-4-((2-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione;

2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione;

2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutyl)amino)isoindoline-1,3-dione;

2-(2,6-dioxopiperidin-3-yl)-4-((5-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione;

2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione;

2-(2,6-dioxopiperidin-3-yl)-4-((7-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione;

3-(4-((2-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

(2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(2-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(3-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-hydroxy-1-((S)-2-(4-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-hydroxy-1-((S)-2-(5-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(1-(5-isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-hydroxy-1-((S)-2-(7-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-hydroxy-1-((S)-2-(8-(4-(1-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-hydroxy-1-((S)-2-(9-(4-(1-(5-isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-4-hydroxy-1-((S)-2-(10-(4-(1-(5-isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

2-((2-((1-(N-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

2-((2-((1-(N-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N-methyl-3,6,9,12-tetraoxapentadecan-15-amide

1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N-methyl-3,6,9,12,15-pentaoxaoctadecan-18-amide;

2-((2-((1-(N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

2-((2-((1-(N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

2-((2-((1-(N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

2-((2-((1-(N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

2-((2-((1-(N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

2-((2-((1-(N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)-N-methylglycyl)-5-methoxyindolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-fluoro-N-methylbenzamide;

(2S,4R)-1-((S)-2-(tert-butyl)-14-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-12-methyl-4,11,14-trioxo-6,9-dioxa-3,12-diazatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-16-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-14-methyl-4,13,16-trioxo-7,10-dioxa-3,14-diazahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N16-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyl-4,7,10,13-tetraoxahexadecanediamide;

N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N19-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyl-4,7,10,13,16-pentaoxanonadecanediamide;

N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methylsuccinamide;

N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methylglutaramide;

N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyladipamide;

N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N7-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methylheptanediamide;

N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyloctanediamide;

N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N9-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methylnonanediamide;

N1-(2-(6-((4-((3-fluoro-2-(methylcarbamoyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)-2-oxoethyl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyldecanediamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-N-methylpropanamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)-N-methylpropanamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methyl-3,6,9,12-tetraoxapentadecan-15-amide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methyl-3,6,9,12,15-pentaoxaoctadecan-18-amide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylacetamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylpropanamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylbutanamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylpentanamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylhexanamide;

N-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-methylheptanamide;

(2S,4R)-1-((S)-12-(tert-butyl)-2-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-3,10-dioxo-5,8-dioxa-2,11-diazatridecan-13-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N19-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyl-4,7,10,13,16-pentaoxanonadecanediamide;

N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methylsuccinamide;

N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyloctanediamide;

N1-(1-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N1-methyldecanediamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;

(2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

(2S,4R)-1-((S)-2-(4-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(6-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(8-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(10-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)-3,5-dimethylpiperazine-1 -carbonyl)phenyl)pyridazine-3 -carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)acetyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-((S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azaheptadecanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-((S)-21-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16-pentaoxa-20-azatricosanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide;

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide; and

6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-((3S,5R)-4-(10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoyl)-3,5-dimethylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide.
A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
The pharmaceutical composition according to claim 39, further comprising at least one additional agent for treating and/or preventing cancer.
The compound of formula (I) according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use as a medicament.
The compound of formula (I) according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of cancer.
The compound for use according to claim 42, wherein the cancer is selected from the group consisting of lung cancer, lymphoma, diffuse large B-cell lymphoma, anaplastic lymphomainterstitial degenerative lymphoma, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor (IMT), colorectal cancer, glioma, glioblastoma, acute myeloid leukemia, and ovarian cancer.
The compound of formula (I) for use according to claim 43, wherein the cancer is selected from the group consisting of: small cell lung cancer, non-small cell lung cancer, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer.
The compound of formula (I) for use according to claim 43, wherein the lung cancer is lung adenocarcinoma.
The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 38 for the manufacture of a medicament for the prevention and/or treatment of a cancer.
The use according to claim 46, wherein the cancer is selected from the group consisting of lung cancer, lymphoma, diffuse large B-cell lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, colorectal cancer, glioma, glioblastoma, acute myeloid leukemia, and ovarian cancer.
The use according to claim 47, wherein the lung cancer is selected from the group consisting of: small cell lung cancer, non-small cell lung cancer, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-positive non-small cell lung cancer, MET-mutated or expanded lung cancer, and EGFR-mutated non-small cell lung cancer.
The use according to claim 47, wherein the lung cancer is a lung adenocarcinoma.
A method for treating or preventing cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 2 to 38, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 39 or 40.
The method according to claim 50, wherein the cancer is selected from the group consisting of lung cancer, lymphoma, diffuse large B-cell lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor (IMT), colorectal cancer, glioma, glioblastoma, acute myeloid leukemia, and ovarian cancer.
The method according to claim 51, wherein the cancer is selected from the group consisting of: small cell lung cancer, non-small cell lung cancer, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC), ROS1-mutation positive non-small cell lung cancer, MET mutated or amplified lung cancer, and EGFR-mutated non-small cell lung cancer.
The method according to claim 51, wherein the lung cancer is a lung adenocarcinoma.
The method according to any one of claims 50 to 53, wherein the compound of formula (I) according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 39 or 40 is administered to the subject by at least one mode of administration selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, Pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous administration.